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Introduction to Biological Membranes

Biological membranes are composed of lipid, protein and carbohydrate that exist in a fluid state. Biological membranes are the structures that define and control the composition of the space that they enclose. All membranes exist as dynamic structures whose composition changes throughout the life of a cell. In addition to the outer membrane that results in the formation of a typical cell (this membrane is often referred to as the plasma membrane), cells contain intracellular membranes that serve distinct functions in the formation of the various intracellular organelles, e.g. the nucleus and the mitochondria. The nucleus and the mitochondria represent unique membrane enclosed organelles given that both are composed of two lipid bilayers. The nuclear membrane is most often referred to as the nucleolemma and is composed of closely associated inner and outer lipid bilayers. The space between the inner and outer nuclear membranes is referred to as the perinuclear space. This space is in contact with the lumen of the endoplasmic reticulum (ER) via connections between the outer nuclear membrane and the ER membranes. The inner and outer nuclear membranes are also connected at thousands of locations via multiprotein complexes that generate pores in the nuclear membrane called nuclear pore complexes. The nuclear pores are through which RNA and proteins are transported. The mitochondrial inner and outer membranes separated by a greater distance than those of the nucleus creating the inner membrane space. The two mitochondrial membranes are also functionally very distinct and subjected to very different transport controls. Whereas the outer mitochondrial membrane is fairly permeable to most small molecules the inner mitochondrial membrane is essentially impermeable and transport across the membrane in either direction requires highly specific transporter proteins.












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Composition and Structure of Biological Membranes

As indicated above, biological membranes are composed of lipids, proteins, and carbohydrates. The carbohydrates of membranes are attached either to lipid forming glycolipids of various classes, or to proteins forming glycoproteins. The lipid and protein compositions of membranes vary from cell type to cell type as well as within the various intracellular compartments that are defined by intracellular membranes. Protein concentrations can range from around 20% to as much as 70% of the total mass of a particular membrane.

The lipids making up components of membranes are of three major classes that includes glycerophospholipids, sphingolipids, and cholesterol. For information on the structures of these different lipid classes see the Lipids page, Lipid Synthesis page, Sphingolipids page and the Cholesterol page. Sphingolipids and glycerophospholipids constitute the largest percentage of the lipid weight of biological membranes. The hydrocarbon tails of these two classes of lipid result in steric limitations to their packing such that they will form disk-like micelles. The structure of these micelles results from the interactions of the hydrophobic tails of the lipids and the exposure of the polar head groups to the aqueous environment. This orientation results in what is referred to as a lipid bilayer and is diagrammed in the figure below. Lipid bilayers are essentially two-dimensional fluids and the lipid components of the bilayer can diffuse laterally and in fact evidence demonstrates that this lateral diffusion occurs readily. The lipid composition of biological membranes exhibits a distinct inner versus outer polarity. For example the cytoplasmic side of the plasma membrane (also referred to as the inner leaflet) is enriched in the aminophospholipids phosphatidylserine (PS) and phosphatidylethanolamine (PE), whereas the exoplasmic side (also referred to as the outer leaflet) is enriched phosphatidylcholine (PC) and sphingomyelin.

Lipids in the bilayer can also undergo transverse diffusion (also called a flip-flop) where the lipid diffuses from one surface to the other. However, because the flip-flop requires the polar head group to pass through the hydrocarbon core of the bilayer the process is extremely rare. Enzymes have been identified that facilitate the flip-flop process and these enzymes (transporter proteins) are referred to as flippases, floppases, and scramblases (phospholipid scramblases, PLSCR). Although flippases and floppases belong to the same family of membrane transporters, flippases are distinguished from floppases by the direction of the catalyzed lipid movement. Flippases are ATP-dependent transporters that catalyze the movement of lipids from the exoplasmic side (outer leaflet) of the membrane to the cytoplasmic side (inner leaflet) while floppases are ATP-dependent transporters that catalyze the reverse reaction. Scramblases are ATP-independent transporters that transport negatively charged phospholipids in either direction across the membrane. Humans express 14 flippase and floppase genes, all of which are members of the ATPase family of membrane transporters, specifically the ATP8, ATP9, ATP10, and ATP11 subfamilies. Humans express five scramblase genes identified as PLSCR1–PLSCR5.

structure of the lipid bilayer of a typical plasma membrane

Structure of the typical lipid bilayer of the plasma membrane. Integral proteins are those that pass through the bilayer. Peripheral proteins are associated with the inner surface of the plasma membrane. Most integral proteins are modified by carbohydrate addition to their extracellular domains. Membranes also contain carbohydrate modified lipids (glycolipids) in addition to the more common phoshopholipids and cholesterol that constitute the bulk of the lipid content of the membrane.

Biological membranes also contain proteins, glycoproteins, and lipoproteins (see the Glycoproteins and Protein Modifications pages). Proteins associated with membranes are of two general types: integral and peripheral. Integral membrane proteins (also called intrinsic proteins) are tightly bound to the membrane through hydrophobic interactions and are inserted into and/or penetrate the lipid bilayer. In contrast, peripheral membrane proteins (also called extrinsic proteins) are only loosely associated with the membrane either through interactions with the polar head groups of the lipids or through interactions with integral membrane proteins. Peripheral membrane proteins are most often, if not exclusively, found on the cytosolic face of the plasma membrane or the lumenal surface of subcellular organelle membranes.

Proteins that are found associated with membranes can also be modified by lipid attachment (lipoproteins). The lipid portion of a lipoprotein anchors the protein to the membrane either through interaction with the lipid bilayer directly or through interactions with integral membrane proteins. Lipoproteins associated with membranes contain one of three types of covalent lipid attachment. The lipids are isoprenoids such as farnesyl and geranylgeranyl residues (see the Protein Modifications page for the mechanism of protein prenylation), fatty acids such as myristic and palmitic acid, and glycosylphosphatidylinositol, GPI (termed glipiated proteins: see the Glycoproteins page for details).

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Activities of Biological Membranes

Although biological membranes contain various types of lipids and proteins, their distribution between the two different sides of the bilayer is asymmetric. As a general example the outer surface of the bilayer is enriched in phosphatidylethanolamine, whereas the intracellular surface is enriched in phosphatidylcholine. Carbohydrates, whether attached to lipid or protein, are almost exclusively found on the external surfaces of membranes. The asymmetric distribution of lipids and proteins in membranes results in the generation of highly specialized sub-domains within membranes. In addition, there are highly specialized membrane structures such as the endoplasmic reticulum (ER), the Golgi apparatus and vesicles. The most important vesicles are those that contain secreted factors. Membrane bound proteins (e.g. growth factor receptors) are processed as they transit through the ER to the Golgi apparatus and finally to the plasma membrane. As these proteins transit to the surface of the cell they undergo a series of processing events that includes glycosylation.

The vesicles that pinch off from the Golgi apparatus are termed coated vesicles. The membranes of coated vesicles are surrounded by specialized scaffolding proteins that will interact with the extracellular environment. There are three major types of coated vesicles that are characterized by their protein coats. Clathrin-coated vesicles contain the protein clathrin and are involved in transmembrane protein, GPI-linked protein and secreted protein transit to the plasma membrane. COPI (COP: coat protein complex I) forms the surface of vesicles involved in the transfer of proteins between successive Golgi compartments and in the process of retrograde transport of proteins back to the ER. COPII forms the surface of vesicles that transfer proteins from the ER to the Golgi apparatus. Clathrin-coated vesicles are also involved in the process of endocytosis such as occurs when the LDL receptor binds plasma LDLs for uptake by the liver. The membrane location of these types of receptors is called a clathrin-coated pit.

In addition, certain cells have membrane compositions that are unique to one surface of the cell versus the other. For instance epithelial cells have a membrane surface that interacts with the lumenal cavity of the organ and another that interacts with the surrounding cells. The membrane surface of cells that interacts with lumenal contents is referred to as the apical surface or domain, the rest of the membrane is referred to as the basolateral surface or domain. The apical and basolateral domains do not intermix and contain different compositions of lipid and protein.

Most eukaryotic cells are in contact with their neighboring cells and these interactions are the basis of the formation of organs. Cells that are touching one another are in metabolic contact which is brought about by specialized tubular particles called junctions. Mammalian cells contain three major types of cell junctions called gap junctions, tight junctions, and adherens junctions.

Gap junctions are intercellular channels designed for intercellular communication and their presence allows whole organs to be continuous from within. One major function of gap junctions is to ensure a supply of nutrients to cells of an organ that are not in direct contact with the blood supply. Gap junctions are formed from a type of protein called a connexin (also called gap junction proteins). Connexin proteins form complexes in the membrane (called connexons) that generate the channels. Humans express a total of 22 gap junction protein genes that are divided into five families identified as GJA-GJE. A related nomenclature uses the designation CX to reflect the name connexin. For example the GJA1 (gap junction protein alpha 1) gene is also known as the CX43 gene.

Tight junctions (also referred to as occluding junctions) are primarily found in the epithelia and endothelia and are designed for occlusion. Tight junctions act as barriers that regulate the movement of solutes and water between various epithelial and endothelial layers. The tight junction serves as a barrier to the paracellular movement of ions and molecules, as well as to the movement of proteins and lipids between the apical and the basolateral domains of the plasma membrane. In addition to forming barrier complexes in the membrane, tight junction proteins also coordinate numerous other signal transduction proteins and intracellular trafficking proteins. At least 40 proteins have been found to be involved in the formation of the various tight junctions. These proteins are divided into four major categories; scaffolding, regulatory, transmembrane, and signaling. The major transmembrane proteins of tight junctions are the protein occludin (encoded by the OCLN gene), the claudin proteins (23 proteins encoded by genes designated CLDN), and the junctional adhesion molecules [JAM; these proteins belong to immunoglobulin (Ig) superfamily].

Adherens junctions are composed of transmembrane proteins that serve to anchor cells via interactions with the extracellular matrix and intracellular proteins that interact with the actin filaments that control cell movement and shape. The major transmembrane proteins of adherens junctions are members of the cadherin family of Ca2+-dependent adhesion molecules. The intracellular proteins of an adherens junction are the α-catenins, γ-catenin (also known as plakoglobin), and δ-catenin (also designated p120). Related to the adherens junctions are the desmosomes and hemidesmosomes that are also involved in membrane anchoring functions.

Given the predominant lipid nature of biological membranes many types of molecules are restricted in their ability to diffuse across a membrane. This is especially true for charged ions, water and hydrophilic compounds. The barrier to membrane translocation is overcome by the presence of specialized channels and transporters. Although channels and transporters are required to move many types of molecules and compounds across membranes, some substances can pass through from one side of a membrane to the other through a process of diffusion. Diffusion of gases such as O2, CO2, NO, and CO occurs at a rate that is solely dependent upon concentration gradients. Lipophilic molecules will also diffuse across membranes at a rate that is directly proportional to the solubility of the compound in the membrane. Although water can diffuse across biological membranes, the physiological need for rapid equilibrium across plasma membranes has led to the evolution of a family of water transporting channels that are called aquaporins (see section below).

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Transmembrane Protein Classes

There are numerous classes of protein that span the membrane of cells, be it the plasma membrane or intracellular organellar membranes. The transmembrane proteins include the various ion channels, other types of channel proteins, transporter proteins, growth factor receptors, and cell adhesion molecules. All transmembrane proteins, regardless of function, are classified dependent upon their structure. There are four main classifications for transmembrane proteins, type I, II, III, and IV. Types I, II, and III are all characterized by passing through the membrane once, referred to as single-pass transmembrane proteins. Type IV transmembrane proteins pass through the membrane several times and, therefore, they are all referred to as multiple-pass transmembrane proteins. Type I transmembrane proteins are anchored to the membrane via a sequence of hydrophobic amino acids referred to as the stop-transfer sequence and this class all have the C-terminus of the protein inside the cell and the N-terminus outside. A typical example of a type I transmembrane protein is the LDL receptor. Type II transmembrane proteins are anchored to the membrane via a signal-anchor sequence and have the C-terminus outside the cell and the N-terminus inside. An example of a type II transmembrane protein is the transferrin receptor. Type III transmembrane proteins do not have a signal sequence and the N-terminus of the protein is outside the cell. An example of a type III transmembrane protein would be any member of the cytochrome P450 family of xenobiotic metabolizing enzymes found in the liver. Type IV transmembrane proteins are typified by the G-protein coupled receptor (GPCR) superfamily of receptor proteins that span the membrane seven times. This class of receptor is often referred to as the serpentine receptor family because of the multiple membrane spans. Another example of a type IV transmembrane protein is the α-subunit of a typical Na+,K+-ATPase (see below). Type IV transmembrane proteins are divided into type IV-A and type IV-B where the IV-A members have the N-terminus inside the cell and the C-terminus outside and the IV-B members are oriented in the opposite direction. The Na+,K+-ATPase α-subunit proteins are type IV-A multi-pass transmembrane proteins, whereas, all GPCRs are members of the type IV-B family.

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Membrane Channels

The definition of a channel (or a pore) is that of a protein structure that facilitates the translocation of molecules or ions across the membrane through the creation of a central aqueous channel in the protein. This central channel facilitates diffusion in both directions dependent upon the direction of the concentration gradient. Channel proteins do not bind or sequester the molecule or ion that is moving through the channel. Specificity of channels for ions or molecules is a function of the size and charge of the substance. The flow of molecules through a channel can be regulated by various mechanisms that result in opening or closing of the passageway. More details on the numerous types of ion channels are discussed in the sections below.

Membrane channels are of three distinct types. The α-type channels are homo- or hetero-oligomeric structures that in the latter case consist of several dissimilar proteins. This class of channel protein has between 2 and 22 transmembrane α-helical domains which explains the derivation of their class. Molecules move through α-type channels down their concentration gradients and thus, require no input of metabolic energy. Some channels of this class are highly specific with respect to the molecule translocated across the membrane while others are not. In addition, there may be differences from tissue to tissue in the channel used to transport the same molecule. As an example, there are 40 different K+-specific voltage-gated channels in humans. The transport of molecules through α-type channels occurs by several different mechanisms. These mechanisms include changes in membrane potential (termed voltage-regulated or voltage-gated), phosphorylation of the channel protein, intracellular Ca2+, G-proteins, and organic modulators.

Aquaporins (AQP) are a family of α-type channels responsible for the transport of water across membranes. At least 14 aquaporin protein encoding genes have been identified in humans (termed MIP, AQP1–AQP11, AQP12A, and AQP12B). MIP is major intrinsic protein of lens fiber and has also been called aquaporin 0 (AQP0). Several AQP genes encode proteins that transport water and glycerol and sometimes other small molecules. These latter aquaporins are also referred to as the aquaglyceroporins. The AQP3, AQP7, and AQP9 genes encode the human aquaglyceroporins.

The aquaporins assemble in the membrane as homotetramers with each monomer consisting of six transmembrane α-helical domains forming the distinct water pore. Probably the most significant location of aquaporin expression is in the kidney. The proximal tubule expresses AQP1, AQP7, AQP8, and AQP11, while the collecting ducts express AQP2, AQP3, AQP4, AQP5, AQP6, and AQP8. Loss of function of the renal aquaporins is associated with several disease states. Mutations in the AQP2 gene are associated with nephrogenic diabetes insipidus (NDI), acquired hypokalemia, and hypercalcemia.

structure of a typical aquaporin

Diagrammatic representations of the structure of an aquaporin. Top pane shows the linear array of the protein indicating the two regions of helical domains that interact to form the three dimensional orientation of the protein. The pore that forms in the aquaporins is composed of two halves referred to as hemipores. Amino acids of the pore that are critical for water transport are the asparagine (N), proline (P) and alanine (A) residues indicated in each hemipore. Bottom panel shows how the two hemipores interact to form the functional aquaporin.

The β-barrel channels (also called porins) are so named because they have a transmembrane domain that consists of β-strands forming a β-barrel structure. Porins are found in the outer membranes of mitochondria. The mitochondrial porins are voltage-gated anion channels that are involved in mitochondrial homeostasis and apoptosis.

The pore-forming toxins represent the third class of membrane channels. Although this is a large class of proteins first identified in bacteria, there are a few proteins of this class expressed in mammalian cells. The defensins are a family of small cysteine-rich antibiotic proteins that are pore-forming channels found in epithelial and hematopoietic cells. The defensins are involved in host defense against microbes (hence the derivation of their name) and may be involved in endocrine regulation during infection.

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Membrane Transporters

Transporters are distinguished from channels because they catalyze (mediate) the movement of ions and molecules by physically binding to and moving the substance across the membrane. Transporter activity can be measured by the same kinetic parameters applied to the study of enzyme kinetics. Transporters exhibit specificity for the molecule being transported as well as show defined kinetics in the transport process. Transporters can also be affected by both competitive and noncompetitive inhibitors. Transporters are also known as carriers, permeases, translocators, translocases, and porters. Mediated transporters are classified based upon the stoichiometry of the transport process. Uniporters transport a single molecule at a time, symporters simultaneously transport two different molecules in the same direction, and antiporters transport two different molecules in opposite directions.

examples of various membrane transport mechanisms

Membrane transport processes. Diagrammatic representation of the various mechanisms for the passage/transport of ions and molecules across biological membranes.

The action of transporters is divided into two classifications: passive-mediated transport (also called facilitated diffusion) and active transport. Facilitated diffusion involves the transport of specific molecules from an area of high concentration to one of low concentration which results in an equilibration of the concentration gradient. Glucose transporters are a good example of passive-mediated (facilitative diffusion) transporters. More information on the different glucose/hexose transporters can be found in the Glycolysis page. Another important class of passive-mediated transporters are the K+ channels (see section above). In contrast, active transporters transport specific molecules from an area of low concentration to that of high concentration. Because this process is thermodynamically unfavorable, the process must be coupled to an exergonic process, most often the hydrolysis of ATP.

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The ATPase Family of Transporters

There are many different classes of membrane transporters that couple the hydrolysis of ATP to the transport of specific molecules. In general these transporters are referred to as ATPases. These ATPases are so named because the ATP hydrolysis that occurs during the transport process is coupled to the autophosphorylation of the transporter. There are four primary types of ATPase transporters that function in eukaryotes. In addition to the four classes of ATPase described in this section, another important class of transporters that function via the use of ATP hydrolytic energy is the ATP-binding cassette (ABC) transporter family. An additional family of functionally diverse ATPase-related proteins is called the AAA ATPase family. The name of this family is derived from ATPases Associated with diverse cellular Activities. The AAA family is commposed of 52 functional genes whose encoded proteins all contain a conserved domain of approximately 230 amino acids. Several members of the AAA family function in the processes of DNA replication, exocytosis and endocytosis, and several are components of the 26S proteosome.

E-type ATPases are cell surface transporters that hydrolyze a range of nucleoside triphosphates that includes extracellular ATP. These transporters derive their nomenclature from the fact that they are invloved in Extracellular transport. The activity of the E-type ATPases is dependent on Ca2+ or Mg2+ and it is insensitive to specific inhibitors of P-type, F-type, and V-type ATPases. The E-type ATPases can hydrolyze other NTPs besides ATP, and some can utilize NDPs. The most common substrates are ATP, ADP, and UTP. There are at least three classes of E-type ATPases.

F-type ATPases function in the translocation of H+ in the mitochondria during the process of oxidative phosphorylation. F-type transporters contain rotary motors. The nomenclature of F-type ATPases derives from phosphorylation Factor. Because these transporters transport H+ they are also referred to as H+-transporting ATPases. Additional common nomenclature for these ATPases is F0F1-ATPase. The F0 subunit is the rotary core of the ATPase that is connected to the F1 catalytic core of the mitochondrial ATP synthase complex.

P-type ATPases are mostly found in the plasma membrane and are involved in the transport of H+, K+, Na+, Ca2+, Cd2+, Cu2+, Mg2+, Co2+, Ag2+, and Zn2+. These transporters represent one of the largest families found in both prokaryotes and eukaryotes. The P-type ATPases are grouped into five classes designated P1–P5 with several classes further divided into subclasses designated A, B, C etc. For example the P2 class contains the A, B, C, and D subclasses. The P-type ATPases contain a core cytoplasmic domain structure that includes a phosphorylation domain (P domain), a nucleotide-binding domain (N domain), and an actuator domain (A domain). The P-type ATPases also possess ten transmembrane helixes termed M1–M10 where helixes M1–M6 comprise the core of the membrane transport domain. The P-type ATPases are also referred to as the E1-E2 ATPases.

V-type ATPases are located in acidic vesicles and lysosomes and have homology to the F-type ATPases and also contain rotary motors like F-type ATPases. The V nomenclature is derived from the fact that these transporters are located in Vacuoles. The V-type ATPases are involved in the processes of neurotransmitter release, protein trafficking, receptor-mediated endocytosis, and active transport of metabolites.

A fifth family of ATPase transporters is the A-type family found only in prokaryotes.

A-type ATPases are Archaeal bacterial transporters that function like the F-type class of ATPases.

Table of the ATPase Family of Transporters

ATPase Family/ Type Function Member Names / Comments
1 / P-type Na+/K+ transporters ATP1A1, ATP1A2, ATP1A3, ATP1A4
the ATP1A genes all encode the catalytic α-subunit of the transporter
the ATP1B genes all encode the regulatory glycoprotein β-subunit of the transporter

ATP1B4: encoded protein in humans does not function as a Na+/K+-ATPase β-subunit, but instead interacts with the nuclear transcriptional co-regulator SNW domain containing 1, SNW1 (also known as SKI-interacting protein, SKIP)
2 / P-type Ca2+ transporters ATP2A1: also known as SERCA1 (sarco/endoplasmic reticulum Ca2+-ATPase); found in cardiac muscle fast twitch fibers
ATP2A2: also known as SERCA2; found in cardiac muscle slow twitch fibers
ATP2A3: also known as SERCA3; ubiquitously expressed in muscle cells

ATP2B1, ATP2B2, ATP2B3, and ATP2B4 are all plasma membrane-associated Ca2+ transporters
ATP2B1: also identified as PCMA1b (plasma membrane Ca2+ transporter 1b)
ATP2B2: also identified as PCMA2a (plasma membrane Ca2+ transporter 2a)
ATP2B3: also identified as PCMA3a (plasma membrane Ca2+ transporter 3a)
ATP2B4: also identified as PCMA4b (plasma membrane Ca2+ transporter 4b)

ATP2C1, ATP2C2 are secretory pathway Ca2+ transporters
4 / P-type H+/K+ transporters ATP4A: encodes the α-subunit of the stomach parietal cell H+ transporter; also identified as the α1 subunit; also expressed in the kidneys; the α2 subunit (encoded by the ATP12A gene) is termed the non-gastric (colonic) transporter which is also expressed in the kidneys
ATP4B: encodes the β-subunit of the stomach parietal cell H+ transporter
5 / F-type H+ transporters, mitochondrial ATP5A1: encodes the α-subunit of mitochondrial F1 (catalytic core) complex
ATP5B: encodes the β-subunit of mitochondrial F1 complex
ATP5C1: encodes the γ-subunit of mitochondrial F1 complex
ATP5D: encodes the δ-subunit of mitochondrial F1 complex
ATP5E: encodes the ε-subunit of mitochondrial F1 complex
ATP5F1: encodes the B1-subunit of mitochondrial F0 (proton channel) complex
ATP5G1: encodes the C1-subunit of mitochondrial F0 complex
ATP5G2: encodes the C2-subunit of mitochondrial F0 complex
ATP5G3: encodes the C3-subunit of mitochondrial F0 complex
ATP5H: encodes the D-subunit of mitochondrial F0 complex
ATP5I: encodes the E-subunit of mitochondrial F0 complex
ATP5J: encodes the F6-subunit of mitochondrial F0 complex
ATP5J2: encodes the F2-subunit of mitochondrial F0 complex
ATP5L: encodes the G-subunit of mitochondrial F0 complex
ATP5L2: encodes the G2-subunit of mitochondrial F0 complex
ATP5O: encodes the O-subunit (OSCP: oligomycin sensitivity-conferring protein) of mitochondrial F0 complex
MT-ATP6: mitochondrially encoded ATP synthase 6
MT-ATP8: mitochondrially encoded ATP synthase 8
6 / V-type H+ transporters, lysosomal ATP6AP1 and ATP6AP2 encode vacuolar (V-type) ATPase accessory proteins
ATP6AP2 encoded protein is also known to bind the hormone renin (and prorenin) resulting in the activation of the conversion of angiotensinogen to angiotensin I

ATP6V1A, ATP6V1B1, ATP6V1B2, ATP6V1C1, ATP6V1C2, ATP6V1D, ATP6V1E1, ATP6V1E2, ATP6V1F, ATP6V1G1, ATP6V1G2, ATP6V1G3, ATP6V1H all encode components of the cytosolic catalytic (V1) complex of V-type ATPases; the V1 complexes are all composed of eight different subunits, three A subunits, three B subunits, two G subunits and the C, D, E, F, and H subunits (A3B3CDEFG2H); the A3B3 hexamer is the catalytic (ATP hydrolysis) complex

ATP6V0A1, ATP6V0A2, ATP6V0A4, ATP6V0B, ATP6V0C, ATP6V0D1, ATP6V0D2, ATP6V0E1, ATP6V0E2; all encode components of the transmembrane (V0) complex of V-type ATPases; the V0 complexes are composed of at least five different subunits identified as a, b, c', c", d, e
7 / P-type Cu2+ transporters ATP7A: encodes the Cu2+-transporting ATPase α-polypeptide; localized to the Golgi to supply copper-dependent enzymes with copper; migrates to plasma membrane to participate in copper efflux when intracellular copper levels are elevated; defects in gene result in Menkes disease
ATP7B: encodes the Cu2+-transporting ATPase β-polypeptide; localized to the Golgi to supply copper-dependent enzymes with copper; migrates to plasma membrane to participate in copper efflux when intracellular copper levels are elevated; particularly important in the export of hepatocyte copper to the bile canaliculi; defects in gene result in Wilson disease
8 / P-type phospholipid transporters ATP8A1, ATP8A2
ATP8B1, ATP8B2, and ATP8B3: involved in phosphatidylserine (PS) and phosphatidylethanolamine (PE) transport from one side of a membrane to the other
ATP8B4: putative phospholipid transporter
9 / P-type putative phospholipid transporters ATP9A, ATP9B
10 / P-type phospholipid transporters ATP10A: involved in phosphatidylserine (PS) and phosphatidylethanolamine (PE) transport; this gene is maternally expressed and is located in the region of chromosome 15 commonly deleted in Angelman syndrome
11 / P-type putative phospholipid transporters ATP11A, ATP11B, ATP11C
12 / P-type H+/K+ transporters, non-gastric ATP12A: originally identifed as the non-gastric (colonic) H+/K+-ATPase; encodes the catalytic subunit of ouabain-sensitive H+/K+-ATPases; also identified as the a2 subunit of H+/K+-ATPases
13 / P-type inorganic cation transporters ATP13A1, ATP13A2, ATP13A3, ATP13A4, ATP13A5
ATP13A2 (also known as PARK9): mutations in gene associated with Kufor-Rakeb syndrome, KRS; KRS is also known as Parkinson disease 9, a juvenile-onset, levodopa-responsive form of the disease

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One of the most thoroughly studied classes of ATPases are the Na+,K+-ATPases found in plasma membranes. These transporters, sometimes called Na+,K+-pumps, are involved in the transport of Na+ out of, and K+ into, cells. The extrusion of Na+ allows cells to control their water content. In addition, the fact that three moles of Na+ are transported out and only two moles of K+ are transported into the cell, an electrochemical gradient is established. This is the basis for the electrochemical excitability of nerve cells. In fact, it is this transporter action that is the major requirement for ATP production from glucose oxidation in the central nervous system.

The Na+,K+-ATPases belong to the P2 class and specifically to the P2C subclass of ATPases. These ATPases are composed of two subunits (α and β). The α-subunit (≈113 kD) binds ATP and both Na+ and K+ ions and contains the phosphorylation sites typical of the P-type ATPases. The autophosphorylation site is the P domain. As discussed below, P-type ATPases are also subject to additional phosphorylation events via other kinases. The smaller β-subunit (≈35 kDa glycoprotein) is absolutely necessary for activity of the complex. It appears to be critical in facilitating the plasma membrane localization and activation of the α-subunit.

Several isoforms of both α- and β-subunits have been identified that exhibit different kinetic parameters and tissue distribution. There are four α-subunit genes (ATP1A1, ATP1A2, ATP1A3, and ATP1A4) and three β-subunit genes in humans (ATP1B1, ATP1B2, and ATP1B3). Another gene identified as ATP1B4 does not encode a β-subunit of Na+,K+-ATPases in placental mammals. The α1 isoform is the predominant form in the kidney but is also ubiquitously expressed. The α2 isoform is primarily expressed in muscle tissues (skeletal, smooth, and cardiac) as well as in adipose tissue, brain, and lung. The α3 isoform is expressed primarily in the heart and neurons. The α4 isoform is only expressed in the testes. The β1 isoform is ubiquitously expressed and is associated with the α1 subunit in the ubiquitously expressed α1β1 Na+,K+-ATPase complex. The β2 isoform is predominantly expressed in neurons and heart cells. The β3 isoform is expressed in testes but has also been detected in early developing neurons.

In addition to the ability to form numerous complexes through the interactions of different α- and β-subunits, the Na+,K+-ATPases also associate with a family of small single transmembrane-spanning proteins termed the FXYD (fix-id) proteins. These proteins get their name from the fact that they all share a signature 35-amino acid homology domain that contains the invariant five amino acid motif: PFXYD derived from the single letter amino acid code. Although the designation X indicates any amino acid can occupy that position, it is in fact usually tyrosine (Y), but can also be glutamate (E), threonine (T), or histidine (H). The human FXYD family of proteins is composed of at least seven members identified as FXYD1–FXYD7. Five members of this family, including FXYD1 (also known as phospholemman), FXYD2 (also known as the γ-subunit of Na+,K+-ATPase), FXYD3 (also known as Mat-8), FXYD4 (also known as corticosteroid hormone-induced factor, CHIF), and FXYD7, are auxiliary subunits of Na+,K+-ATPases and they regulate Na+,K+-ATPase activity in a tissue- and isoform-specific way. FXYD5 is also known as dysadherin and FXYD6 is also known as phosphohippolin.

membrane organization of Na-K-ATPase subunits

Two-dimensional view of Na+,K+-ATPases. Organization of the α- and β-subunits of Na+,K+-ATPases in the plasma membrane showing how the individual proteins span the membrane several times. The FXYD2 subunit  (also known as the γ-subunit) which is found associated with some isoforms of Na+,K+-ATPase is also shown.

functional organization of Na-K-ATPase subunits

Three-dimensional view of Na+,K+-ATPases. Functional organization of the α- and β-subunits of Na+,K+-ATPases, along with the FXYD2 subunit, in the plasma membrane. The movement of two moles of K+ into the cell as three moles of Na+ are transported out is shown. Associated with ion transport is the hydrolysis of ATP by the α-subunit which provides the energy to drive the process.

When Na+,K+-ATPases have ATP bound they can bind intracellular Na+ ions. The hydrolysis of the ATP results in the phosphorylation of an Asp residue in the conserved DKTGT motif present in P domain of the α-subunit of all P-type ATPases. Autophosphorylation of P-type ATPases occurs as a function of the nucleotide binding (N domain) domain. The phosphorylation of this Asp residue results in release of ADP. The phosphorylation of the pump results in a conformational change which exposes the Na+ ions to the outside of the cell and they are released. The pump then binds two extracellular K+ ions which stimulates dephosphorylation of the α-subunit that in turn allows the pump to bind ATP again. Dephosphorylation results as a consequence of the P domain interacting with the actuator domain (A domain) which contains a catalytic Glu residue in a conserved TGE motif. The dephosphorylation and ATP binding causes the pump to reorient to its original conformation and releases the K+ ions inside the cell. At this point the pump is capable of release of Na+ ions again.

In addition to the autophosphorylation site in the P domain of Na+,K+-ATPases, these pumps are subject to additional regulatory phosphorylation events catalyzed by PKA and PKC. The stimulus for PKA and PKC-mediated phosphorylation of Na+,K+-ATPases is activation of associated receptors. Adrenergic, cholinergic, and dopaminergic receptor agonists result in PKA-mediated phosphorylation of the pumps. Activation of the prostaglandin E receptors has also been shown to lead to PKA-mediated phosphorylation of neuronal Na+,K+-ATPases. The most studied site of PKA phosphorylation is a serine residue (Ser943) that is found in a domain between two transmembrane domains in the α1 isoform of the pump. PKA-mediated phosphorylation results in reduced activity of the pump but also results in increased levels of the pump in the plasma membrane. The N-terminus of the α1 isoform has been shown to be phopshorylated by PKC although no obvious conserved consensus site is present. Serine 16 is the only conserved serine residue in the N-terminus of the α1 subunit and mutation of this residue abolishes PKC-mediated phosphorylation. As indicated above, several members of the P-type ATPases form complexes with proteins of the FXYD family. In the heart and in skeletal muscle FXYD1 has been shown to be a target for PKA and PKC phosphorylation. Whereas, PKA-mediated phosphorylation of the α1 subunit of the pump reduces its transport activity, PKA-mediated phosphorylation of FXYD1 results in increased activity of associated Na+,K+-ATPases. This indicates that unmodified FXYD1 serves as an inhibitor of the pump.

The Na+,K+-ATPases are also receptors for the endogenous cardiotonic steroids as well as certain toxins from plants and amphibians. Binding of these various compounds to the pump results in activation of various kinases such as Src and PI3K resulting in modulation of cell adhesion and growth. Endogenous cardiotonic steroids (also referred to as cardiac glycosides) are specific inhibitors of Na+,K+-ATPases and have been isolated from adrenal glands, heart tissue, the hypothalamus, and cataractous lenses. Pregnenolone and progesterone are the precursors in the biosynthesis of endogenous ouabain (also identified as g-strophanthin) and endogenous digoxin. Ouabain and digoxin are referred to as cardenolides. Exogenous ouabain is a poisonous compound found in the ripe seeds of the African plant Strophanthus gratus and the bark of Acokanthera ouabaio. Another class of endogenous cardiotonic steroids is the bufadienolides which includes marinobufagenin, marinobufotoxin (the C3-site arginine-suberoyl ester of marinobufagenin), telocinobufagin (the reduced form of marinobufagenin), and 19-norbufalin. There are indications that many more endogenous cardiotonic steroids may exist in mammals. Unlike its role in endogenous oubain synthesis progesterone does not appear to be a precursor of marinobufagenin. However, mevastatin (a statin drug that inhibits HMG-CoA reductase), reduces the biosynthesis of marinobufagenin, indicating that cholesterol is a precursor of bufadienolides in mammals.

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Ion Channels

Ion channels, including those that are ligand- or voltage-gated are found in all cellular membranes including the plasma membrane and intracellular organelle membranes. The ion channels represent a large class of proteins, and multiprotein complexes, that form pores within membranes that allow the flow of ions across the membrane. The ion channels are broadly classified into six large families channel proteins or channel complexes. These six families consist of the calcium channels, chloride channels, potassium channels, the sodium channels, the gap junction proteins, and the porins (includes the aquaporins discussed above). Within the broad context of the six large families of ion channels, there are numerous distinct subfamilies. The calcium channel family includes the cation channels sperm associated (CatSper) subfamily, the voltage-gated calcium channels, the IP3 receptors, the ryanodine receptors, and the two pore segment channels. The chloride channel family includes the calcium-activated chloride channels, the voltage-gated chloride channels, the intracellular chloride channels, and the ATP-gated chloride channel (CFTR). The gap junction protein channel family includes the connexins and the pannexins. The potassium channel family includes the calcium-activated potassium channels, the voltage-gated potassium channels, the voltage-gated potassium subfamily J channels, the sodium-activated potassium subfamily T channels, and the two pore potassium subfamily K channels. The porin channel family includes the aquporins and the voltage-dependent anion channels. The sodium channel family includes the acid sensing ion channel subunits, the epithelial sodium channels, the sodium leak channels, and the voltage-gated sodium channels.

Not all ion channels are gated such as is the case for certain K+ and Cl channels, the TRP (transient receptor potential) superfamily of cation channels, the ryanodine receptors and the IP3 receptors. However, many ion channels are gated such as is the case for most Na+, K+ Ca2+ and some Cl channels which are all gated by voltage. The non-voltage-gated ion channels can, however, be gated but the gating is controlled by second messengers and other intracellular and/or extracellular mediators. The clinical significance of ion channels is without question and currently, this large class of membrane transporter represents one of the largest targets for existing drugs, second only to G-protein coupled receptor (GPCR) targeting drugs.

In addition to the voltage-gated ion channels there is another large family of gated ion channels defined as the ligand-gated channels. These channels are regulated in response to ligand binding such as is the case for numerous neurotransmitters. These ligand gated neurotransmitter receptors are referred to as ionotropic receptors. Numerous neurotransmitters bind to ionotropic receptors such as glutamate, acetylcholine, glycine, GABA, and serotonin. More details on the actions of these neurotransmitters and their respective receptors can be found in the Biochemistry of Nerve Transmission page.

Table of Several Ion Channel Family Members

Ion Channel Family Family Member Genes Comments
Acid-sensing (proton-gated): ASIC ASIC1, ASIC3, ASIC3 these genes encode the acid sensing subunits of a subfamily of sodium channels; primarily expressed in central and peripheral neurons; involved in neuronal sensitivity to acidosis; found associated with receptors for nociception (pain) and taste, with photoreceptors, and in cochlear hair cells, testis, pituitary gland, lung epithelial cells, urothelial cells, adipose cells, vascular smooth muscle cells, immune cells, and bone; activation of ASIC channels in the brain is associated with the response to neuronal injury caused by focal ischemia and to axonal degeneration in autoimmune inflammation
Aquaporins AQP0, AQP1, APQ2, APQ3, APQ4, APQ5, APQ6, APQ7, APQ8, APQ9, APQ10 represent a subfamily of the porin channel family; discussed above
Calcium channels numerous genes in several subfamilies the calcium channels represent a large diverse family of proteins involved in calcium ion transport across a membrane; there are five subfamilies

1: calcium channels sperm associated (CatSper): four primary genes (CATSPER1–CATSPER4); three auxiliary subunit genes: CATSPERB (β-subunit), CATSPERD (δ-subunit), CATSPERG (γ-subunit)
2: voltage-gated calcium channel (Cav) subunits: 26 genes comprising primary alpha1(α1)-subunits (ten genes) and auxiliary beta(β) subunits (four genes); alpha2/delta(α2δ) subunits (four genes); gamma(γ) subunits (eight genes)
3: ryanodine receptors: RYR1, RYR2, RYR3 (see in Table below)
4: inositol-1,4,5-trisphosphate (IP3) receptors; three genes: ITPR1, ITPR2, ITPR3; these receptors are ligand-gated Ca2+ channel (details in Signal Transduction page)
5: two pore segement channels: TPCN1, TPCN2
CatSper CATSPER1, CATSPER2, CATSPER3, CATSPER4 represent a subfamily of voltage-gated calcium channels; required for proper movement of spermatozoa
Chloride channels numerous genes in several subfamilies the chloride channels represent a large diverse family of proteins involved in chloride ion transport across a membrane; there are four subfamilies

1: calcium-activated channels: the anoctamins (10 genes: ANO1–ANO10) and the bestrophins (four genes: BEST1–BEST4)
2: voltage-gated chloride channels: 9 channel coding genes (CLCN1–CLCN7, CLCNKA, CLCNKB); CLCNKA and CLCNKB proteins function in association with a β-subunit called barttin encoded by the BSND gene
3: intracellular chloride channels: CLIC1–CLIC6
4: chloride channel ATP-gated: more commonly known as the cystic fibrosis transmembrane conductance regulator: CFTR
Connexins and Pannexins 21 connexin genes (designated with GJ) and 3 pannexin genes represent the gap junction ion channel family
connexin family composed of alpha(α) protein (seven genes, GJA), beta(β) proteins (seven genes, GJB), gamma(γ) proteins (three genes, GJC), delta(δ) proteins (three genes, GJD), epsilon(ε) proteins (one gene GJE1)
the pannexins (PANX1, PANX2, PANX3) are related to the invertebrate gap junction proteins identified as the innexins
Cylic nucleotide-gated channels CNGA1, CNGA2, CNGA3, CNGA4, CNGB1, CNGB3, HCN1, HCN2, HCN3, HCN4 non-selective cation channels that are responsible for signaling in the primary sensory neurons of the visual (photoreceptors) and olfactory systems (olfactory sensory neurons, OSN) as well as activation of action potentials in cardiac muscle

alpha(α)-subunit genes are CNGA1–CNGA4
beta(β)-subunit genes are CNGB1 and CNGB2

HCN genes encode the hyperpolarization-activated cyclic nucleotide-gated ion channels; control the rhythmic pacemaker depolarizations in cardiac and neuronal cells
IP3 receptors ITPR1, ITPR2, ITPR3 specialized calcium channels that are present in the membranes of the endoplasmic reticulum, ER; activated in response to the binding of inositol-1,4,5-trisphosphate (IP3) which is released from membrane phosphatidylinositol-4,5-bisphosphate (PIP2) following GPCR-activation of phospholipase Cβ, PLCβ
Potassium channels numerous genes in several subfamilies the potassium channels represent a large family of diverse channels that are divided into five subfamilies:

1: calcium-activated potassium channels (Kca): KCNMA1, KCNN1, KCNN2, KCNN3, KCNN4, KCNU1; the KCNMA1 gene encodes the α-subunit of what are commonly called the big potassium (BK) channels or MaxiK channels; the KCNMA1 encoded protein forms a complex with one of four possible β-subunits encoded by the KCNMB1, KCNMB2, KCNMB3, or KCNMB4 gene; although the KCNU1 gene is included in the Ca2+-activated K+ channel subfamily it is not activated by Ca2+ but is activated by high pH
2: voltage-gated potassium channels (Kv): 40 genes comprising subfamilies A (eight genes), B (two genes), C (four genes), D (three genes), F (one gene), G (four genes), H (eight genes), Q (five genes), S (three genes), V (two genes); KCNA4 and KCND3 genes encode subunits of the outward rectifying K+ channels involved in cardiac myocyte action potentials
3: voltage-gated potassium subfamily J channels; also identified as inwardly rectifying K+ channels (Kir): 16 genes KCNJ1–KCNJ6, KCNJ8–KCNJ16, KCNJ18; KCNJ1 is commonly called ROMK (renal outer medullary K+ channel); KCNJ8 (Kir6.1) and KCNJ11 (Kir6.2) are ATP-sensitive channels; KCNJ11 forms the core of the ATP-sensitive K+ channel in pancreatic β-cells that regulates the secretion of insulin; KCNJ3 (Kir3.1), KCNJ5 (Kir3.4), KCNJ6 (Kir3.2), and KCNJ9 (Kir3.3) are activated via their coupling to GPCRs that when activated lead to release of the βγ subunits of the associated G-protein that then activate the K+ channel, these KCNJ members are, therefore, also referred to a G protein-coupled inwardly-rectifying potassium channels (GIRK) where KCNJ3 is GIRK1, KCNJ6 is GIRK2, KCNJ9 is GIRK3, and KCNJ5 is GIRK4
4: sodium-activated potassium subfamily T channels: KCNT1, KCNT2
5: two pore potassium subfamily K channels (also known as potassium leak channels): 15 genes KCNK1–KCNK7, KCNK9, KCNK10, KCNK12, KCNK13, KCNK15–KCNK18
Ryanodine receptors RYR1, RYR2, RYR3 specialized intracellular ligand-gated calcium release channels; involved in the release of sarcoplasmic reticulum (SR) stored Ca2+ in response to muscle stimulation; also present in numerous other cell types and participate in neurotransmission and secretory processes
Sodium channels numerous genes in several subfamilies the sodium channels represent a large family of diverse channels that are divided into four subfamilies:

1. voltage-gated sodium channels: composed of large pore-forming α-subunit and small accessory β-subunit that modulates activity of the α-subunit; nine α-subunit genes SCN1A–SCN5A, SCN8A–SCN11A; four β-subunit genes SCNB1–SCNB4
2. acid sensing ion channel subunits; five genes ASIC1–ASCI5
3. epithelial sodium channels; four genes SCNN1A (α-subunit), SCNN1B (β-subunit), SCNN1D (δ-subunit), SCNN1G (γ-subunit)
4. sodium leak channel; one gene NALCN
Transient receptor potential (TRP) channels represents a superfamily of voltage- and/or ligand-gated cation channels involved in physical and chemical sensory processing; divided into six subfamilies: TRPC, TRPV, TRPA, TRPM, TRPML, TRPP TRPC: canonical; seven genes: TRPC1–TRPC7 (TRPC2 is pseudogene in humans)
TRPV: vanilloid; six genes: TRPV1–TRPV6
TRPA: ankyrin; one gene: TRPA1
TRPM: melastatin; eight genes: TRPM1–TRPM8
TRPML: mucolipin (genes designated MCOLN); three genes: MCOLN1–MCOLN3
TRPP: polycystin (genes designated PKD); three genes: PKD2, PKD2L1, PKD2L2
Voltage-dependent anion channels VDAC1, VDAC2, VDAC3 represent a subfamily of porin channels; these channels are located on the outer mitochondrial membrane where they facilitate small molecule and ion exchange between the mitochondria and the cytosol

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Ligand-Gated Ion Channels

The ligand-gated ion channel (LGIC) superfamily of ion channels represents a large family of channel proteins/protein complexes that mediate the regulated flow of selected ions across the plasma membrane in response to ligand-specific binding. Ion movement through the channel is a passive process driven by the energy of the electrochemical gradient for the ion. As the name implies, the LGIC are opened, or gated, by the binding of an appropriate ligand, which is, most often, a neurotransmitter. In addition to gating of the channels in response to ligand binding, there is modulation of the gating process by the binding of endogenous, or exogenous, modulators to allosteric sites. The large LGIC superfamily of channels that are all activated (gated) by extracellular ligands can be subdivided into ten families of structurally related channels, several of which are also outlined in the section above covering ion channels. These ten families are the ionotropic 5-hydroxytryptamine (5-HT3: serotonin) receptors, nicotinic acetylcholine receptors (nAChR), the ionotropic glutamate receptors, the GABA-A receptors, the glycine receptors (GlyR), the IP3 receptors, the ATP-gated channel (CFTR), the ryanodine receptors (RYR), the purinergic (P2X) receptors, and the zinc-activated channel (ZAC). Several ligand-gated channels have a common motif in their extracellular domains that is the result of an intrachain disulfide bond. These channels are referred to as the Cys-loop family of channels. Members of the Cys-loop family include the nAChR, the GlyR, the 5-HT3 receptors, the GABA-A receptor subunits, and the zinc-activated channel. The ionotropic glutamate receptors are the AMPA (GluA), NMDA (GluN), kainate (GluK), and delta (GluD) receptors.

Table of Ligand-Gated Ion Channel Family Members

Ligand-Gated Channel/Receptor Family Family Member Genes Comments
Serotonin: 5-HT3 receptors HTR3A, HTR3B, HTR3C, HTR3D, HTR3E see the Biochemistry of Nerve Transmission page
GABA-A receptor subunit 18 different subunit genes: six alpha(α)-subunit genes [GABRA1–GABRA6]; three beta(β)-subunit genes [GABRB1–GABRB3]; one delta(δ)-subunit gene [GABRD]; one epsilon(ε)-subunit gene [GABRE]; three gamma(γ)-subunit genes [GABRG1–GABRG3]; one pi(π)-subunit gene [GABRP]; one theta(θ)-subunit gene [GABRQ]; two rho(ρ)-subunit genes [GABRR1, GABRR2] the minimal composition for a function GABA-responsive receptors is the inclusion of an α- and a β-subunit; the most common GABA-A receptor in the brain is a heteropentameric structure: α2β2γ
details covered in the Biochemistry of Nerve Transmission page
Glycine receptors four α-subunit genes: GLRA1, GLRA2, GLRA3, GLRA4; 1 β-subunit gene: GLRB see the Biochemistry of Nerve Transmission page
Glutamate receptors: ionotropic four receptor families: AMPA (GluA) four genes, NMDA (GluN) seven genes, Kainate (GluK) five genes, and Delta (GluD) two genes AMPA: GRIA1, GRIA2, GRIA3, GRIA4
Kainate: GRIK1, GRIK2, GRIK3, GRIK4, GRIK5
Delta: GRID1, GRID2
details covered in the Biochemistry of Nerve Transmission page
Nicotinic acetylcholine receptors 16 different subunit genes: nine alpha(α)-subunit genes [CHRNA1–CHRNA7, CHRNA9, CHRNA10]; four beta(β)-subunit genes [CHRNB1, CHRNB2, CHRNB3, CHRNB4]; one delta(δ)-subunit gene [CHRND]; one epsilon(ε)-subunit gene [CHRNE]; one gamma(γ)-subunit gene [CHRNG] see the Biochemistry of Nerve Transmission page
Purinergic (P2X) receptors P2RX1, P2RX2, P2RX3, P2RX4, P2RX5, P2RX6, P2RX7 represent a family of ATP-gated non-selective channels; transport Na+, K+, and Ca2+ ions; form homo- and heterotrimeric channels; channels are expressed in numerous excitatory and non-excitatory cells that includes neurons, glia cells, platelets, epithelial cells, and macrophages; involved in many physiological and pathological processes, including synaptic transmission, pain perception, inflammation, cardiovascular modulation, immunomodulation and tumorigenesis

another family of purinergic recptors is the P2Y family which is composed of nucleotide-activated G-protein coupled receptors, GPCR
IP3 receptors ITPR1, ITPR2, ITPR3 see the Signal Transduction page
Ryanodine receptors RYR1, RYR2, RYR3 see the Biochemistry of Muscle page
ATP-gated receptor (CFTR) CFTR expressed in cells that are responsible for the production of mucus, sweat, saliva, tears, and digestive enzymes; mutations in the gene responsible for cyctic fibrosis
Zinc-activated channel (ZAC) ZACN channel is a member of the Cys-loop superfamily of ligand-gated ion channels; primarily activated by Zn2+ but may also be spontaneously activated

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Calcium Channels

Calcium is a critical metal (as the Ca2+ ion) in numerous biochemical and physiological processes. In order for Ca2+ to exert its multiple effects, its entry into cells and storage within cells must be tightly regulated. Much of the membrane transport of Ca2+ into and out of cells, and into and out of intracellular organelles is controlled by a large family of voltage-gated calcium channels. In addition, neuronal and striated and skeletal muscle excitation involves local depolarization of the plasma membrane (termed the sarcolemma in muscle cells) and the activation of voltage-gated calcium channels allowing Ca2+ ion movement across the membrane. The voltage-gated calcium channels (also called voltage-dependent calcium channels, VDCC) are divided into three distinct families, each with multiple members. These channel families are termed the Cav1, Cav2, and Cav3 families. The Cav1 and Cav2 families represent the high voltage activated (HVA) channels while the Cav3 family represents the low voltage activated (LVA) family.

Nearly all of the voltage-gated calcium channels are pentameric structures composed of five different protein subunits identified as the α1-, α2-, β-, γ, and δ-subunits. Some voltage-gated calcium channels are composed of only four subunits and lack the γ subunit. These latter four subunit channels are typical of cardiac voltage-gated calcium channels. The α1-subunit is the actual transmembrane channel through which the Ca2+ ions flow. The α2- and the δ-subunits are derived from a single preproprotein that, following cleavage, forms an extracellular disulfide bonded glycoprotein dimer designated α2/δ. The γ-subunit is a transmembrane glycoprotein and the β-subunit is an intracellular protein. It is the distinct α1-subunits that define the various Cav1, Cav2, and Cav3 channel types. There are four different β-subunit encoding genes identified as CACNB1, CACNB2, CACNB3, and CACNB4. The α2/δ preproprotein is encoded by the CACNA2D1 gene. An alternative splice variant mRNA from the CACNA2D1 gene lacks the δ-subunit portion of the preproprotein. There are eight genes encoding γ-subunit proteins which are identified as the CACNG1–CACNG8 genes.

There are four members of the Cav1 channel family (also referred to as L-type calcium channels) identified as Cav1.1, Cav1.2, Cav1.3, and Cav1.4. The designation of these calcium channels as L-type refers to the initial characterization of these channels being Long-lasting channels. A high degree of variability exists in the Cav1 channel family due to multiple genes encoding the various protein subunits as well as due to alternative splicing of the mRNAs derived from these genes. Humans express four distinct α1-subunit genes that form the various Cav1 calcium channels. These four genes are identified as CACNA1S (forms the core of the Cav1.1 channel), CACNA1C (forms the core of the Cav1.2 channel), CACNA1D (forms the core of the Cav1.3 channel), and CACNA1F (forms the core of the Cav1.4 channel).

All of the Cav2 family member proteins are found within the central nervous system (CNS). There are three Cav2 family member channels identified as Cav2.1 (also called the P/Q-type channel), Cav2.2 (N-type channel), and Cav2.3 (R-type channel). The designation of P/Q-type calcium channels refers to the initial characterization of these channels in Purkinje cells. The N-type calcium channels are so-called since they are enriched in Neuronal cells. The three α1-subunit genes that encode the three unique proteins of the Cav2 channels are identified as CACNA1A (forms the core of the Cav2.1 channel), CACNA1BC (forms the core of the Cav2.2 channel), and CACNA1E (forms the core of the Cav2.3 channel). All of the Cav2 type Ca2+ channels are responsible for the initiation of synaptic transmission at fast synapse in the nervous system.

There are three members of the Cav3 family (Cav3.1, Cav3.2, and Cav3.3) which are also referred to as the T-type calcium channels. The designation of these calcium channels as T-type refers to the initial characterization of these channels being Transient opening channels. The three α1-subunit genes that encode the three unique proteins of the Cav3 channels are identified as CACNA1G (forms the core of the Cav3.1 channel), CACNA1H (forms the core of the Cav3.2 channel), and CACNA1I (forms the core of the Cav3.3 channel). The Cav3 channels are expressed in the brain, kidney, and heart. These calcium channels are involved in many important physiological functions including neuronal firing, smooth muscle contraction, hormone secretion, and cardiac muscle cell activity. The Cav3 channels in the heart are abundant in sinoatrial (SA) node cells and Purkinje fibers. The neuronal Cav3 channels generate low-threshold action potentials that lead to nerve transmission oscillations that are prominent in the thalamus.

Within striated muscle cells, Ca2+ entry across the sarcolemma causes the initiating neural stimulus to spread to the associated T-tubule (transverse tubule) system and deep into the interior of the myofiber. T-tubule depolarization spreads to the sarcoplasmic reticulum (SR: muscle form of the endoplasmic reticulum, ER), with the effect of the opening of calcium release channels in the SR membranes. These calcium release channels belong to the family of ligand-gated ion channels. The SR calcium release channels are also known as the ryanodine receptor (RYR) due to the fact that they were originally identified by their high affinity for the plant alkaloid ryanodine. There are several RYR genes in humans with the RYR1 gene being the predominantly expressed member in skeletal muscle. The RYR2 gene is highly expressed in cardiac myocytes. The activation of the SR calcium release channel leads to a massive, rapid movement of calcium from the lumen (cisternal compartment) of the SR into the sarcoplasm close to nearby myofilaments. The appearance of calcium very close to the TnC subunit of the troponin complex results in the production of multiple myosin power strokes, as long as the available calcium concentration remains greater than about 1μM–5μM.

Calcium is also critical in the cessation of contractile activity and the accompanying state of relaxation in striated muscle. When the initiating signal for muscle contraction is removed, the myocytes need to reverse the localization of the activating calcium from the sarcoplasm back into the SR. Sarcoplasmic calcium is pumped back into the lumen of the SR by an extremely active ATP–driven calcium pump, which comprises one of the main proteins of the SR membrane. This SR calcium pump is a member of a family of Ca2+-ATPases identified as sarco/endoplasmic reticulum Ca2+-ATPases (SERCA) as outlined in the Table above. The human SERCA proteins are encoded by a family of three genes identified as the ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting (ATP2A) genes. These three genes are identified as ATP2A1, ATP2A2, and ATP2A3. For each ATP hydrolyzed by the SR Ca2+-ATPase, two calcium ions are moved out of the sarcoplasm into the SR lumen. Alterations in smooth muscle cytosolic calcium levels also occur via voltage-dependent activation processes and also by receptor-mediated processes. The voltage-mediated processes involve the activation of plasma membrane Cav1 channels as in the case of striated muscle cells. In vascular and visceral smooth muscle cells the predominant α1 subunit of the channel is α1C (encoded by the CACNA1C gene) forming the Cav1.2 type calcium channel. However, in some smooth muscle types the α1D isoform (encoded by the CACNA1D gene) is also expressed forming the Cav1.3 type calcium channel.

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The ABC Family of Transporters

The ABC transporters comprise the ATP-binding cassette transporter superfamily. All members of this superfamily of membrane proteins contain a conserved ATP-binding domain and use the energy of ATP hydrolysis to drive the transport of various molecules across all cell membranes. There are 48 known members of the ABC transporter superfamily and they are divided into seven subfamilies based upon phylogenetic analyses. These seven subfamilies are designated ABCA (ABC1), ABCB (also called TAP/MDR for transporter, ATP cassette), ABCC (also called MRP for multidrug resistance protein), ABCD (also called ALD for adrenoleukodystrophy), ABCE (also called OABP for oligoadenylatre-binding protein), ABCF (also called GCN20), and ABCG (also called White). Each member of a given subfamily is distinguished with numbers (e.g. ABCA1). The ABCA subfamily comprises 12 genes identified as ABCA1–ABCA10, ABCA12, and ABCA13 (ABCA11 and ABCA17 are psuedogenes). The ABCB subfamily comprises 11 genes identified as ABCB1, ABCB4-ABCB11, TAP1 and TAP2 (also known as ABCB2 and ABCB3, respectively). The ABCC subfamily comprises 13 genes identified as ABCC1–ABCC6, ABCC8–ABCC13, and CFTR (less commonly identified as ABCC7). The ABCD subfamily comprises 4 genes identified as ABCD1–ABCD4. The ABCE subfamily contains a single gene, ABCE1. The ABCF subfamily comprises three genes identified as ABCF1–ABCF3. The ABCG subfamily comprises five genes identified as ABCG1, ABCG2, ABCG4, ABCG5, and ABCG8.

Gene Symbol Other Names Gene Location / Structure Functions/Comments
ABCA1 ABC1 9q31.1 / 58 exons involved in cellular cholestreol efflux; transfers cellular cholesterol and phospholipids to HDLs (reverse cholesterol transport); defects in gene associated with development of Tangier disease
ABCA2 ABC2 9q34.3 / 50 exons role in delivery of LDL-derived free cholesterol to the endoplasmic reticulum for esterification; involved in protection against reactive oxygen species, drug resistance
ABCA3 ABC3 16p13.3 / 33 exons role in delivery of LDL-derived free cholesterol to the endoplasmic reticulum for esterification; involved in protection against reactive oxygen species, drug resistance
ABCA4 ABCR, ABC10 1p22.1 / 50 exons expressed exclusively in retinal photoreceptors; in association with the process of phototransduction toxic metabolites can accumulate and this transporter is involved in the efflux of the toxic compound N-retinylidene-phosphatidylethanolamine from photoreceptor cells; mutations in this gene are associated with Stargardt disease which is an autosomal recessive form of macular degeneration
ABCA5 ABC13 17q24.3 / 39 exons clustered on chromosome 17 with ABCA6, ABCA8, ABCA9, and ABCA10; function unknown
ABCA6   17q24.2-q24.3 / 44 exons clustered on chromosome 17 with ABCA5, ABCA8, ABCA9, and ABCA10; may be involved in lipid homeostasis in macrophages
ABCA7 ABCX 19p13.3 / 47 exons function unknown but may be involved in lipid homeostasis of immune cells
ABCA8   17q24.2 / 42 exons clustered on chromosome 17 with ABCA5, ABCA6, ABCA9, and ABCA10; may be involved in myelin maintenance
ABCA9   17q24.2 / 42 exons clustered on chromosome 17 with ABCA5, ABCA6, ABCA8, and ABCA10; function unknown
ABCA10   17q24.2 / 40 exons clustered on chromosome 17 with ABCA5, ABCA6, ABCA8, and ABCA9; function unknown
ABCA12   2q35 / 55 exons function unknown
ABCA13   7p12.3 / 75 exons function unknown
ABCB1 P-GP, PGY1, MDR1 7p21.12 / 29 exons PGY1: P-glycoprotein 1; MDR1: multidrug resistance protein 1; is a multidrug resistance P-glycoprotein; is an integral component of the blood-brain barrier, transports a number of drugs from the brain back into the blood
TAP1 ABCB2, PSF1, APT1 6p21.32 / 12 exons TAP1: transporter, ATP-binding cassette, major histocompatibility complex (MHC) 1; PSF1: peptide supply factor 1; APT1: antigen peptide transporter1; functions as a heterodimer with TAP2/ABCB3 to transport cytosolic peptide fragments across the ER into the membrane compartment where MHC class I molecules assemble
TAP2 ABCB3, PSF2, APT2 6p21.32 / 13 exons TAP2: transporter, ATP-binding cassette, major histocompatibility complex (MHC) 2; PSF2: peptide supply factor 2; APT2: antigen peptide transporter1; functions as a heterodimer with TAP1/ABCB2 to transport cytosolic peptide fragments across the ER into the membrane compartment where MHC class I molecules assemble
ABCB4 PGY3, MDR3 17q21.12 / 31 exons PGY3: P-glycoprotein 3; MDR3: multidrug resistance protein 3; is a class III multidrug resistance P-glycoprotein; canalicular phospholipid translocator; biliary phosphatidylcholine transport; defects in gene associated with 6 liver diseases: progressive familial intrahepatic cholestasis type 3 (PFIC3), adult biliary cirrhosis, transient neonatal cholestasis, drug-induced cholestasis, intrahepatic cholestasis of pregnancy, and low phospholipid-associated cholelithiasis syndrome
ABCB5   7p21.1 / 31 exons expressed in limbal stem cells; required for corneal development; originally identifed as a marker for melanoma stem cells and skin progenitor cells
ABCB6 MTABC3 2q35 / 19 exons mitochondrial transporter involved in heme biosynthesis; transports porphyrins into mitochondria; represents the Langereis blood group antigen
ABCB7 ASAT Xq13.3 / 16 exons transport of heme from mitochondria to the cytosol; iron-sulfur (Fe/S) cluster transport; ASAT is X-linked sideroblastic anemia with ataxia
ABCB8 MABC1 7q36.1 / 17 exons MABC1: mitochoindrial ATP-binding cassette 1; present in the inner mitochondrial membrane; involved in organic and inorganic molecule transport out of the mitochondria
ABCB9 TAPL 12q24.31 / 20 exons TAPL: TAP-like; transports a broad spectrum of peptides from the cytosol into the lumen of the lysosomes; transported peptides range fro 6 to 59 amino acids with optimum size shown to be 23 amino acids
ABCB10   1q42.13 / 15 exons function unknown but may be involved in mitochondrial heme transport
ABCB11 BSEP, SPGP 2q31.1 / 30 exons BSEP: bile salt export protein, bile salt transport out of hepatocytes; SPGP: sister of P-glycoprotein; mutations in ABCB11 gene associated with progressive familial intrahepatic cholestasis type 2 (PFIC2)
ABCC1 MRP1 16p13.11 / 34 exons MRP1: multidrug resistance associated protein 1; transport of cobalamin from intestinal enterocytes to the blood; sphingosine-1-phosphate (S1P) release from mast cells which enhances their migration; uses glutathione as a co-factor in mediating resistance to heavy metal oxyanions
ABCC2 MRP2, CMOAT 10q24.2 / 34 exons MRP2: multidrug resistance associated protein 2; CMOAT: canalicular multispecific organic anion transporter; biliary excretion of many non-bile organic anions; gene defects result in Dubin-Johnson syndrome
ABCC3 MRP3, CMOAT2, MOATD 17q21.33 / 32 exons MRP3: multidrug resistance associated protein 3; CMOAT2: canalicular multispecific organic anion transporter; involved in drug resistance; MOATD: multispecific organic anion transporter D
ABCC4 MRP4, MOATB 13q32.1 / 36 exons MRP4: multidrug resistance associated protein 4; MOATB: multispecific organic anion transporter B; enriched in prostate; regulator of intracellular cyclic nucleotide levels; mediator of cAMP-dependent signal transduction to the nucleus
ABCC5 MRP5, MOATC 3q27.1 / 36 exons MRP5: multidrug resistance associated protein 5; MOATC: multispecific organic anion transporter C; resistance to thiopurines and antiretroviral nucleoside analogs
ABCC6 MRP6, MOATE, PXE 16p13.11 / 34 exons MRP6: multidrug resistance associated protein 6; MOATE: multispecific organic anion transporter E; PXE: pseudoxanthoma elasticum, a rare disorder in which the skin, eyes, heart, and other soft tissues become calcified
CFTR ABCC7 7q31.2 / 32 exons CFTR: cystic fibrosis transmembrane conductance regulator; chloride ion channel; gene defects result in cystic fibrosis (CF) with the most common mutation being a three base deletion that removes the Phe residue at position 507, identified as the ΔF507 mutation
ABCC8 SUR 11p15.1 / 39 exons SUR: sulfonylurea receptor; four copies of the ABCC8 encoded proteins associate with four copies of the ATP-sensitive potassium channel encoded by the KCNJ11 gene; the ABCC8 encoded protein is the target of the type 2 diabetes drugs such as glipizide
ABCC9 SUR2 12p12.1 / 42 exons forms part of an ATP-sensitive potassium channel in cardiac, skeletal, and smooth muscle cells; alternative splicing yields two major isoforms, SUR2A includes exon 38A while SUR2B includes exon 38B; mutations in ABCC9 gene associated with cardiomyopathy dilated type 1O
ABCC10 MRP7 6p21.1 / 26 exons MRP7: multidrug resistance associated protein 7; likely to be involved in lipophilic anion efflux
ABCC11 MRP8 16q12.1 / 39 exons MRP8: multidrug resistance associated protein 8; involved in bile acid (glycocholate and taurocholate) uptake, glutathione S-conjugated steroid uptake, and cyclic nucleotide efflux; ABCC11 and ABCC12 derived via gene duplication, both reside at 16q12.1
ABCC12 MRP9 16q12.1 / 29 exons MRP9: multidrug resistance associated protein 9; ABCC11 and ABCC12 derived via gene duplication, both reside at 16q12.1; function unknown
ABCC13   21q11.2 / 7 exons function unknown
ABCD1 ALD Xq28 / 11 exons ALD: adrenoleukodystrophy; involved in the import and/or anchoring of very long-chain fatty acid-CoA synthetase (VLCFA-CoA synthetase) to the peroxisomes; gene defects result in X-linked adrenoleukodystrophy (XALD)
ABCD2 ALDR 12q12 / 13 exons ALDR: adrenoleukodystrophy-related protein; also found in peroxisomal membranes; modifier that contributes to phenotypic variability seen in XALD; can restore peroxisomal fatty acid oxidation defect of XALD liver cells
ABCD3 PMP70, PXMP1 1p21.3 / 28 exons PMP70: peroxisomal membrane protein 70 kDa; also called peroxisomal membrane protein 1; mutation associated with Zellweger syndrome 2 (ZWS2); transports branched-chain fatty acids and C-27 bile acids into the peroxisomes
ABCD4 PMP69, PXMP1L 14q24.3 / 20 exons PMP69: peroxisomal membrane protein 69 kDa; related to the other ABCD family members but localized to ER membranes; also called peroxisomal membrane protein 1-like; mutations increase severity of XALD; may be involved in release of vitamin B12 from the lysosomes to the cytosol
ABCE1 OABP, RNS4I 4q31.21 / 18 exons OABP: oligoadenylate binding protein; RNS4I: ribonuclease 4 inhibitor; may be involved in the regulation of mRNA turnover; antagonizes the anti-viral effects of the interferon-regulated 5'-phosphorylated 2',5'-linked oligoadenylates that bind and activate RNaseL
ABCF1   6q21.33 / 25 exons may be a ribosomal protein involved in mRNA translation
ABCF2   7q36.1 / 17 exons function unknown
ABCF3   3q27.1 / 21 exons may exert antiviral effects against flavivirues such as West Nile virus
ABCG1 White1 21q22.3 / 20 exons involved in mobilization and efflux of intracellular cholesterol; responsible for approximately 20% of cholesterol efflux from macrophages to HDLs (reverse cholesterol transport, RCT)
ABCG2 ABCP, MXR, BCRP 4q22.1 / 20 exons ABCP: ATP-binding cassette transporter, placenta-specific; MXR: mitoxantrone-resistance protein; BCRP: breast cancer resistance protein; xenobiotic transporter; plays a major role in multidrug resistance; heme and protoporphyrin IX export from mitochondria; is a major uric acid secretion transporter in the small intestine; involved in kidney uric acid excretion as well
ABCG4 White2 11q23.3 / 17 exons expression restricted to astrocytes and neurons; cholesterol and sterol efflux to HDL-like particles in the CNS, may function in sterol transport with ABCG1 in cells where the two genes are co-expressed; may increase lipidation of apoE in Alzheimer disease
ABCG5 Sterolin-1 2p21 / 15 exons forms an obligate heterodimer with ABCG8; expressed in intestinal enterocytes and hepatocytes; functions to limit plant sterol and cholesterol absorption from the diet by facilitating efflux out of enterocytes into the intestinal lumen and out of hepatocytes into the bile canaliculi; tandemly arrayed in head-to-tail orientation with ABCG8 gene
ABCG8 Sterolin-2 2p21 / 14 exons see above for ABCG5

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The Solute Carrier Family of Transporters

The solute carrier (SLC) family of transporters includes over 300 proteins functionally grouped into 52 families. The SLC family of transporters includes facilitative transporters, primary and secondary active transporters, ion channels, and the aquaporins. The aquaporins are so named because they constitute water channels (see above). Given the scope of this discussion it is not possible to cover all of the transporters in each of the 52 families. Listed below are several of the families of SLC transporters and within each family is a description of several member proteins. All of the members of a particular family are not included due to space limitations. Focus is primarily on solute carriers discussed on other web pages in this site or due to known clinical significance.

With respect to the numerous amino acid transporters represented in the SLC superfamily of transporters, there is a set of historical nomenclature designations. Neutral amino acid transporters that prefer leucine and other large hydrophobic neutral amino acids are called system L transporters, those that prefer alanine and other small and polar neutral amino acids are called the system A transporters, and those that prefer alanine, serine, and cysteine are called the system ASC transporters. A distinct nomenclature has been used for systems mediating transport of cationic amino acids [system y+ or written y(+)] and those transporting anionic amino acids (system X). Amino acid transporters that are Na+-independent are named with lowercase acronymns, whereas Na+-dependent transporters are named with uppercase acronymns.

SLC Family Functional Class Gene Designations / Comments
1 high affinity glutamate and neutral amino acid transporters SLC1A – SLC1A7

SLC1A1: also called Excitatory Amino Acid Transporter 3 (EAAT3); is a high affinity glutamate transporter; also transports aspartate and cystine
SLC1A2: also called EAAT2; clears glutamate from the synaptic cleft of glutamatergic neurons; decreased expression is associated with amyotrophic lateral sclerosis (ALS: Lou Gehrig disease); also transports aspartate
SLC1A3: high affinity glutamate transporter in glutamatergic neurons; also known as EAAT1; also transports aspartate
SLC1A4: neutral amino acid transporter; also known as ASCT1 (derived from AlaSerCys Transporter 1); transports alanine, serine, and cysteine
SLC1A5: neutral amino acid transporter primarily responsible for glutamine transport; also known as ASCT2; also transports alanine, serine, threonine, and cysteine
SLC1A6: also called EAAT4; is a high affinity glutamate transporter; also transports aspartate; expressed in Purkinje cells of cerebellum
SLC1A7: also called EAAT5; is a high affinity glutamate transporter; also transports aspartate; expressed in bipolar cells and retinal rod cells
2 facilitative GLUT transporters SLC2A1 – SLC2A14

SLC2A1 is GLUT1: glucose and dehydroascorbate (vitamin C) transporter; ubiquitously expressed in various tissues but only at low levels in liver and skeletal muscle; is the primary glucose transporter in brain, placenta, and erythrocytes; is primarily responsible for glucose transport across the blood-brain-barrier (BBB); mutations in the SLC2A1 gene result in GLUT1 deficiency syndrome
SCL2A2 is GLUT2: this glucose transporter is expressed predominantly in the liver, pancreatic β-cells, kidney, and intestines
SCL2A3 is GLUT3: glucose and dehydroascorbate (vitamin C) transporter; primarily expressed in neurons and possess the lowest Km for glucose of any of the glucose transporters
SLC2A4 is GLUT4: glucose and dehydroascorbate (vitamin C); predominantly expressed in insulin-responsive tissues such as skeletal muscle and adipose tissue
SLC2A5 is GLUT5: the major fructose transporter
SLC2A6 is GLUT6: glucose transporter
SLC2A7 is GLUT7: glucose and fructose transporter
SLC2A8 is GLUT8: transports glucose and fructose; highly expressed in oxidative tissues such as the liver; is essential in the development of fructose-induced macrosteatosis in the liver; sensitive to insulin like GLUT4; also transports dehydroascorbate (vitamin C)
SLC2A9 is GLUT9: also known as URATv1; is a major uric acid transporter in the liver and kidneys; two alternatively spliced mRNAs generate two protein isoforms, GLUT9a and GLUT9b
SLC2A10 is GLUT10: glucose and galactose transporter
SLC2A11 is GLUT11: glucose and fructose transporter
SLC2A12 is GLUT12: glucose transporter; sensitive to insulin like GLUT4
SCL2A13: also called the proton (H+) myo–inositol cotransporter, HMIT
SLC2A14 is GLUT14: glucose transporter
3 heavy subunits of heteromeric amino acid transporters
activator of dibasic and neutral amino acid transporters

SLC3A1 encodes one of the heavy chain subunits of heteromeric amino acid transporters; also known as rBAT; forms the renal cystine transporter necessary for cystine reabsorption by the proximal tubules of the kidney along with the light chain subunit encoded by the SLC7A9 gene; defects in this transporter can found in type I cystinurias
SLC3A2 encodes a heavy chain subunit of heteromeric amino acid transporters; also known as 4F2hc; forms heterodimers with the light chain subunits SLC7A5(LAT1); SLC7A6(y+LAT2); SLC7A7(y+LAT1); SLC7A10(ASC1); SLC7A11(xCT)
4 sodium bicarbonate transporters (NBC); anion exchangers (AE) SLC4A1 – SLC4A5, SLC4A7 – SLC4A11

SLC4A1: also known as anion exchanger 1 (AE1) and BND3 (band 3 of red cell membranes); responsible for Cl and HCO3 exchange in the connecting tubules of kidney and in erythrocytes (the "chloride shift"); mutations associated with autosomal recessive and dominant forms of renal tubular acidosis (type 1 RTA)
SLC4A2: also known as AE2; involved in biliary bicarbonate excretion
SLC4A3: also known as AE3
SLC4A4 (NBC1): multiple splice variants identified as NBCe1-A (proximal tubule of kidney: also identified as kNBC1), NBCe1-B (pancreas: also identified as pNBC1), and NBCe1-C (brain); mutations associated with renal tubular acidosis (type 2 RTA)
SLC4A5: also known as NBC4 and NBCe2
SLC4A7 (mNBC3 and NBC2 variant): was formerly identified as SLC4A6 and so the SLC4A6 identity is no longer used
SLC4A8: also known as NBC3; regulation of pH in neurons
SLC4A9 (AE4): expression restricted to kidney
SLC4A10: regulates intracellular pH of neurons
SLC4A11: Na+-borate co-transporter; mutations associated with corneal endothelial dystrophy
5 sodium glucose co–transporters (SGLT) SLC5A1 – SLC5A12

SLC5A1: commonly called SGLT1; is a Na+-dependent intestinal glucose and galactose transporter; H+-coupled glucose transport can also be carried out
SLC5A2: commonly called SGLT2 which is responsible for the majority of Na+-dependent glucose re-absorption by the kidneys and as such is a current target of therapeutic intervention in the hyperglycemia associated with type 2 diabetes; is a low affinity but high capacity glucose transporter
SLC5A3: is a Na+-myoinositol glucose co-transporter (SMIT); ubiquitously expressed with highest levels in endothelial cells, kidney, and thyroid gland
SLC5A4: also known as the Na+-dependent amino acid transporter 1 (SAAT1); also identified as SGLT3; expressed in cholinergic neurons, the small intestine, and skeletal muscle; acts as a glucose sensor which depolarizes the membrane when at high concentration
SLC5A5: Na+-iodide co-transporter commonly identified as NIS; mutations associated with thyroid dyshormonogenesis
SLC5A6: Na+-dependent pantothenate, biotin, and lipoic acid transporter; also identified as Na+-multivitamin transporter (SMVT)
SLC5A7: Na+- and Cl-dependent choline transporter for choline uptake into cholinergic neurons
SLC5A8: lactate, monocarboxylate, and short-chain fatty acid transporter; also known as Na+-monocarboxylate transporter 1 (SMCT1); present in apical membranes of proximal tubule epithelial cells; also transports niacin; is a tumor suppressor that is silenced by hypermethylation in certain colorectal carcinomas
SLC5A9: commonly called SGLT4; is a Na+-dependent mannose and fructose transporter; highly expressed in small intestine and kidney
SLC5A10: commonly called SGLT5; Na+-dependent sugar transporter; high affinity for mannose and fructose; low affinity for glucose and galactose; expressed in the kidney
SLC5A11: commonly called SGLT6; myo-inositol and glucose transporter; highly expressed in the brain
SLC5A12: lactate transporter also known as the Na+-monocarboxylate transporter 2 (SMCT2); present in apical membrane of proximal tubule epithelial cells
6 sodium– and chloride–dependent neurotransmitter transporters SLC6A1 – SLC6A20

SLC6A1: GABA transporter in GABAergic neurons and elsewhere in the brain; commonly called GAT1 (GABA Transporter 1)
SLC6A2: major norepinephrine transporter in the brain and in adrenal medulary chromaffin cells; also transports dopamine
SLC6A3: major dopamine transporter in dopamineric neurons
SLC6A4: is the serotonin transporter; defects in this gene are associated with obsessive-compulsive disorder and anxiety-related traits; the tricyclic antidepressants function principally by inhibiting this transporter in the brain
SLC6A5: glycine transporter in glycinergic neurons and other tissues in the periphery; commonly called GLYT2
SLC6A6: taurine and β-alanine transporter
SLC6A7: proline transporter
SLC6A8: is the creatine transporter by which neurons and skeletal muscle cells take up the compound that was produced in the liver
SLC6A9: glycine transporter; commonly called GLYT1
SLC6A11: GABA transporter; commonly called GAT3
SLC6A13: GABA transporter; commonly called GAT2
SLC6A14: neutral and cationic amino acid transporter
SLC6A15: proline, leucine, valine, isoleucine, and methionine transporter; protein also called system B0 neutral amino acid transporter 2 (B0AT2, or B0AT2)
SLC6A18: glycine, alanine, methionine, serine, cysteine transporter; protein also called system B0 neutral amino acid transporter 3 (B0AT3, or B0AT3)
SLC6A19: involved in neutral amino acid transport, deficiency results in Hartnup disorder; protein also called system B0 neutral amino acid transporter 1 (B0AT1, or B0AT1)
SLC6A20: proline, hydroxyproline, and betaine transporter
7 cationic amino acid transporters [y+ system] and the glycoprotein-associated amino acid transporters SLC7A1 – SLC7A11, SLC7A13, SLC7A14

SLC7A1: arginine, lysine and ornithine transporter; also called cationic amino acid transporter 1, CAT1
SLC7A2: arginine, lysine and ornithine transporter; also called CAT2
SLC7A3: arginine, lysine and ornithine transporter; also called CAT3
SLC7A4: arginine transporter; also called CAT4
SLC7A5: also called L-type (or light subunit) amino acid transporter 1, LAT1
SLC7A6: also called y+L-type amino acid transporter 2, y+LAT2
SLC7A7: also called y+L-type amino acid transporter 1, y+LAT1
SLC7A8: also called L-type amino acid transporter 2, LAT2

LAT1, y+LAT1, and y+LAT2 are the light chains of the heterodimeric amino acid transporters that are disulfided bonded to the heavy chain subunit identified as 4F2hc (encoded by the SLC3A2 gene)

SLC7A9 is the gene encoding the light chain subunit [b(0,+)AT] of the renal cystine transporter that, in association with the heavy chain subunit called rBAT (encoded by the SLC3A1 gene), forms the transporter responsible for cystine reabsorption in the proximal tubules of the kidney and can be defective in cystinurias (referred to as non

-type I)

SLC7A10: encodes the light chain subunit (ASC-1) that associates with 4F2hc (SLC3A1) forming a heteromeric neutral amino acid transporter; transports alanine, cysteine, glycine, serine, and threonine
SLC7A11: encodes the light chain subunit (XCT) of a Na+-independent, Cl-dependent cysteine-glutamate antiporter; also transports aspartate
8 K+-dependent Na+/Ca2+ exchangers (NCX) SLC8A1(NCX1), SLC8A2(NCX2), SLC8A3(NCX3), SLC8B1(NCLX)

SLC8A1: primary transporter for Ca2+ extrusion from cardiac myocytes allowing return to the resting state
SLC8A3: regulates electrogenic Na+ and Ca2+ exchange across plasma membrane and intracellular membranes
SLC8B1: formerly identified as SLC24A6
9 Na+/H+ exchangers (NHE) SLC9A1(NHE1), SLC9A2(NHE2), SLC9A3(NHE3), SCL9A4(NHE4), SLC9A5(NHE5), SLC9A6(NHE6), SLC9A7(NHE7), SLC9A8(NHE8), SLC9A9(NHE9)

SLC9A1: expressed in proximal tubule of kidney and intestines
SLC9A2: involved in Na+ uptake from the colon
SLC9A3: major proximal tubule transporter for Na+ and HCO3 reabsorption with H+ efflux; excretion of H+ from intestinal cells; mutations associated with congenital secretory sodium diarrhea
SLC9A4: expressed in proximal tubule of kidney and intestines
SLC9A6: localized to endosomal membranes where it regulates pH and volume; mutations associated with X-linked Christianson-type syndromic mental retardation
SLC9A8: expressed in proximal tubule of kidney and intestines; highest level of expression iun neonate
SLC9A9: mutations associated with ADHD and autism susceptibility 16
10 sodium bile salt co-transporters SLC10A1, SLC10A2, SLC10A3, SLC10A4, SLC10A5, SLC10A6(SOAT), SLC10A7

SLC10A1: also called NTCP for Na+-taurocholate cotransporting polypeptide; involved in hepatic uptake of bile acids through the sinusoidal/basolateral membrane
SLC10A2: also called ASBT for apical sodium bile salt co-transporter; primary bile acid transporter for uptake into enterocytes of the distal ileum
SLC10A3, SLC10A4, and SLC10A5 are considered orphan transporters
SLC10A6: commonly identified as Na+-dependent organic anion transporter (SOAT); transporter of sulfated steroids and sulfated bile acids
11 proton-coupled metal ion transporters SLC11A1, SLC11A2, SLC11A3

SLC11A1: divalent metal transporter; primarily iron and manganese; involved in iron homeostasis; involved in host resistance to pathogens
SLC11A2 is also known as the divalent metal-ion transporter-1 (DMT1)
SLC11A3 is now referred to as SLC40A1, this protein is more commonly called ferroportin, but is also known as iron-regulated gene 1 (IREG1), and reticuloendothelial iron transporter (MTP1)
12 electroneutral cation/Cl co-transporters SLC12A1 – SLC12A9

SLC12A1: expressed almost exclusively in the thick ascending limb of the loop of Henle in the kidney; commonly identified as Na+-K+-Cl co-transporter type 2 (NKCC2)
SLC12A2: encodes the Na+-K+-Cl co-transporter type 1; commonly identified as NKCC1; ubiquitously expressed; functions in the distal convoluted tubule and the collecting ducts in the kidney
SLC12A3: renal thiazide (diuretic used to treat hypertension)-sensitive Na+-Cl co-transporter (commonly identified as NCC) expressed in the distal convoluted tubule of kidney; mutations in gene cause Gitelman syndrome (hypokalemic alkalosis with hypomagnesemia)
13 Na+–sulfate/carboxylate co-transporters SLC13A1, SLC13A2, SLC13A3, SLC13A4, SLC13A5

SLC13A1: apical membrane transporter; involved in renal sulfate homeostasis in proximal tubule of kidney; also identified as NaS1 (Na+-sulfate transporter 1)
SLC13A2: citrate transporter in proximal tubule of kidney and intestine; also indentified as NaDC1 (Na+-dicarboxylate transporter 1)
SLC13A3: also called Na+-dicarboxylate cotransporter 3 (NaDC3); transports citrate, succinate, 2-oxoglutarate in proximal tubule of kidney, liver, brain, and pancreas
14 urea transporters SLC14A1 (UT-B): erythrocyte urea transporter; UT-B1 and UT-B2 isoforms
SLC14A2 (UT-A): renal Na+-independent urea transporter; six protein isoforms in mammals with UT-A1, UT-A2, UT-A3, and UT-A6 isoforms expressed in humans
15 proton oligopeptide co-transporters SLC15A1, SLC15A2, SLC15A3, SLC15A4

SLC15A1: transport di- and tripeptides (but not free amino acids) from small intestine into enterocytes and peptide reabsorption in proximal tubule of kidney; also identified as PepT1
SLC15A2: peptide and peptide-like drug transporter expressed in apical membranes of proximal tubule cells; also identified as PepT2
PepT1 and PepT2 transport 400 di-peptides and 8000 tri-peptides as well as synthetic drugs; PepT1 shows higher affinities than does PepT1; peptide transport is coupled to Na+/H+ exchange
SLC15A3 (PHT2) and SLC15A4 (PHT1) mediate egress of bacterial peptides from dendritic cells of immune system
16 monocarboxylate transporters (MCT) SLC16A1 (MCT1), SLC16A2 (MCT8), SLC16A3 (MCT4), SLC16A4 (MCT5), SLC16A5 (MCT6), SLC16A6 (MCT7), SLC16A7 (MCT2), SLC16A8 (MCT3), SLC16A9 (MCT9), SLC16A10, SLC16A11 (MCT11), SLC16A12 (MCT12), SLC16A13 (MCT13), SLC16A14 (MCT14)

SLC16A1, SLC16A3, and SLC16A7: plasma membrane lactate and ketone body transporters; also transports pyruvate but only across the plasma membrane
SLC16A9: lactate transporter
SLC16A10 (TAT1: T-type amino acid transporter): Na+-independent aromatic amino acid transporter
17 organic anion transporters; originally identified as type I Na+–phosphate co-transporters (NPT) SLC17A1 – SLC17A9

SLC17A1 (NPT1): expressed in apical membrane of proximal tubule cells in kidney; involved in uric acid efflux into urine
SLC17A2 (NPT3): was misidentifed as NPT2 which is encoded by the SLC34A1 gene
SLC17A3 (NPT4): expressed in apical membrane of proximal tubule cells in kidney; involved in uric acid efflux into urine
SLC17A4: expressed in apical membrane of intestinal enterocytes; involved in lumenal phosphate uptake
SLC17A5: sialic acid efflux transporter
SLC17A6, SLC17A7, and SCL17A8 are glutamate transporters in the brain
SLC17A9: involved in vesicular uptake, storage, and secretion of ATP
18 vesicular amine transporters SLC18A1, SLC18A2, SLC18A3

SLC18A1and SLC18A2 both function in vesicular accumulation of monoamines; both are targets of reserpine (anti-hypertensive and antipsychotic) and tetrabenazine (treatment of tremors in Huntington disease)
SLC18A3: functions to accumulate acetylcholine into secretory vesicles
19 folate/thiamine transporters SLC19A1, SLC19A2, SLC19A3

SLC19A1: cellular uptake of reduced folate and thiamine mono- and di-phosphate but not free thiamine
SLC19A2: intestinal uptake of thiamine
SLC19A3: cellular uptake of thiamine; mutations in gene associated with a Wernicke-like encephalopathy
20 type III Na+–phosphate co-transporters SLC20A1, SLC20A2

SLC20A1: commonly called Pit-1 [inorganic (Pi) phosphate transporter 1]
SLC20A2: commonly called Pit-2
organic anion transporting polypeptides (OATP) the SLC21 genes are all identified as SLCO genes; there are 12 human SLCO family member genes divided into 6 subfamilies identified as 1 through 6; these transporter genes have the nomenclature SLCO followed by the family number, subfamily letter, and member number; the proteins encoded by the SLCO genes are identified as organic anion transporting polypeptides (OATP)

SLCO1A2 (SLC21A3): protein is OATP1A2; Na+-independent bile acid transporter in kidney, intestines, liver, and brain; also transports folate; formerly OATPA
SLCO1B1 (SLC21A6): protein is OATP1B1; basolateral membrane Na+-independent liver-specific bile acid transporter; also transports folate; formerly OATPC
SLCO1B3 (SLC21A8): protein is OATP1B3; liver-specific Na+-independent liver-specific bile acid and bilirubin transporter as well as xenobiotics
SLCO1B7 (SLC21A21)
SLCO1C1 (SLC21A14): protein is OATP1C1; Na+-independent thyroid hormone uptake into brain; formerly OATPF
SLCO2A1 (SLC21A2): protein is OATP2A1; prostaglandin transporter
SLCO2B1 (SLC21A9): protein is OATP2B1; formerly OATPB
SLCO3A1 (SLC21A11): protein is OATP3A1; formerly OATPD
SLCO4A1 (SLC21A12); protein is OATP4A1; formerly OATPE
SLCO4C1 (SLC21A20): protein is OATP4C1; transports bile acids, peptides, certain drugs, conjugated steroids, thyroid hormones; formerly OATPX
SLCO5A1 (SLC21A15): protein is OATP5A1; formerly OATPJ
SLCO6A1: protein is OATP6A1; formerly OATPY
22 organic cation transporters (OCT), zwitterion/cation transporters (OCTN) and organic anion transporters (OAT) SLC22A1 (OCT1), SLC22A2 (OCT2), SLC22A3 (OCT3), SLC22A4 (OCTN1), SLC22A5 (OCTN2), SLC22A6 (OAT1), SLC22A7 (OAT2), SLC22A8 (OAT3), SLC22A9 (OAT7), SLC22A10 (OAT5), SLC22A11 (OAT4), SLC22A12 (URAT1), SLC22A13 (OAT10), SLC22A14 (OCTL2), SLC22A15, SLC22A16, SLC22A17, SLC22A18, SLC22A20 (OAT6), SLC22A23, SLC22A24, SLC22A25, SLC22A31

SLC22A5 (OCTN2): required for active cellular uptake of carnitine
SLC22A6 (OAT1): uric acid transporter involved in uric acid uptake from blood into proximal tubule cells of kidney
SLC22A7 (OAT2): uric acid transporter involved in uric acid uptake from blood into proximal tubule cells of kidney
SLC22A8 (OAT3): uric acid transporter involved in uric acid uptake from blood into proximal tubule cells of kidney
SLC22A11 (OAT4): present in apical membrane proximal tubule of cells of kidney; involved in uric acid reabsorption
SLC22A12 (URAT1): the major uric acid transporter for urate reabsorption in the apical membrane of proximal tubule cells of kidney; target for uricosuric drugs (e.g. probenecid, benzobromarone)
SLC22A13 (OAT10): uric acid transporter present in apical membrane proximal tubule cells of kidney
SLC22A16 is also called carnitine transporter 2, CT2
SLC22A18: found in the imprinted region of chromosome 11 associated with Beckwith-Wiedemann syndrome (BWS)
23 Na+–dependent vitamin C cotransporters (SVCT) SLC23A1(SVCT1), SLC23A2(SVCT2), SLC23A3(SVCT3)

SLC23A1: found in intestinal and renal epithelial cells where it is responsible for ascorbic acid uptake from the diet and reabsorption within the proximal tubules of the kidneys, respectively
SLC23A2: present in the plasma membrane of all nucleated cells, responsible for ascorbate uptake from the blood
24 Na+/(Ca2+–K+) exchangers (NCKX) SLC24A1(NCKX1), SLC24A2(NCKX2), SLC24A3(NCKX3), SLC24A4(NCKX4), SLC24A5(NCKX5)

SLC24A1: expressed in platelets and rod photoreceptors; mutations cause congenital stationary night blindness
SLC24A2: expressed in retinal cone cells and brain; mediates light-induced decreases in free Ca+
SLC24A4: involved in skin, hair, and eye pimentation
SLC24A5: involved in skin, hair, and eye pimentation; mutations are associated with oculotaneous albinism type VI
25 mitochondrial carriers SLC25A1 – SLC25A53

SLC25A1 is an inner mitochondrial membrane citrate transporter
SLC25A2 (ORNT2) is an ornithine transporter
SLC25A3 is an inner mitochondrial membrane phosphate-proton (H+) symporter
SLC25A4, SLC25A5, and SLC25A6 are mitochondrial ADP/ATP (adenine nucleotide) transporters
SLC25A7 is uncoupling protein 1 (UCP1)
SLC25A8 is uncoupling protein 2 (UCP2)
SLC25A9 is uncoupling protein 3 (UCP3)
SLC25A10 is a dicarboxylic acid transporter
SLC25A11 is an inner mitochondrial membrane malate and 2-oxoglutarate (α-ketoglutarate) transporter
SLC25A12 (aralar) transports aspartate out of the mitochondria in exchange for glutamate; also called aspartate- glutamate carrier 1 (AGC1)
SLC25A13 is also called citrin, transports aspartate out of mitochondria in exchange for glutamate; also called aspartate-glutamate carrier 2 (AGC2); mutations in gene associated with type II citrullinemia (CTLN2)
SLC25A14 is a UCP-related protein identifed as brain mitochondrial carrier protein or UCP5
SLC25A15 (ORNT1) is an ornithine transporter; also transports citrulline, arginine, and lysine; mutations in gene are associated with hyperornithinemia-hyperammonemia-homocitrullinemia syndrome
SLC25A16 is also known as a Graves disease autoantigen
SLC25A18 and SLC25A22 are inner mitochondrial membrane glutamate/H+ symporters
SLC25A19 transports thiamine pyrophosphate (TPP) into mitochondria; also identified as mitochondrial thiamine pyrophosphate transporter (MTPPT)
SLC25A20 is also called carnitine-acylcarnitine translocase (CACT)
SLC25A27 is uncoupling protein 4 (UCP4)
SLC25A29 is mitochondrial ornithine transporter 3 (ORNT3)
26 multifunctional anion exchangers SLC26A1 – SLC26A11; SLC26A10 is pseudogene

SLC26A1: also known as SAT1 (sulfate anion transporter 1); hepatic, renal, and intestinal sulfate and oxalate transporter; mutations in gene cause hyperoxaluria and formation of calcium oxalate kidney stones
SLC26A2: chloride and sulfate transporter which is mutated in diastrophic dysplasia (DTD) which is associated with undersulfation of proteoglycans in cartilage matrices
SLC26A3: essential for intestinal chloride uptake
SLC26A4: also called pendrin, expressed at significant levels in the thyroid gland where it is involved in iodine homeostasis and thyroid hormone biosynthesis; also functions in chloride and bicarbonate transport in kidney and ear epithelial cells; mutations in gene result in Pendred syndrome (PDS) which is associated with the most common form of syndromal deafness, also results in enlarged vestibular aqueduct and goiter
SLC26A5: also called prestin, is a motor protein of cochlear outer hair cells
SLC26A6: chloride and bicarbonate transporter in kidney, intestines, and pancreas
SLC26A7: chloride, sulfate, and bicarbonate transporter in gastric parietal cells
SLC26A8: epxpression restricted to spermatocytes
SLC26A9: chloride and bicarbonate transporter in gastric parietal cells, airway epithelial cells, and kidney
27 fatty acid transporters (FATP) SLC27A1 (FATP1), SLC27A2 (FATP2), SLC27A3 (FATP3), SLC27A4 (FATP4), SLC27A5 (FATP5), SLC27A6 (FATP6)

FATP1 is also known as acyl-CoA synthetase very long-chain family, member 5 (ACSVL5); broad specificity for long and very long chain fatty acids; transports C16:0, C18:1, C20:4, and C24:0
FATP2 is also known as acyl-CoA synthetase very long-chain family, member 1 (ACSVL1) and very long-chain acyl-CoA synthetase (VLACS or VLCS); transports C16:0, C24:0, bile acids, and cholestanoic acids
FATP3 is also known as acyl-CoA synthetase very long-chain family, member 3 (ACSVL3); transports multiple long chain fatty acids
FATP4 is also known as acyl-CoA synthetase very long-chain family, member 4 (ACSVL4); transports C18:1 and C20:4
FATP5 is also known as acyl-CoA synthetase very long-chain family, member 6 (ACSVL6) and very long-chain acyl-CoA synthetase-related protein (VLACSR) or very long-chain acyl-CoA synthetase homolog 2 (VLCSH2); transports multiple long chain fatty acids
FATP6 is also known as as acyl-CoA synthetase very long-chain family, member 2 (ACSVL2) and very long-chain acyl-CoA synthetase homolog 1 (VLCSH1): transport preference for C16:- and C18:0; will not transport fats less than 10 carbons

FATP function is discussed in the Fatty Acid Oxidation page
28 Na+–dependent concentrative nucleoside transport (CNT) SLC28A1(CNT1), SLC28A2(CNT2), SLC28A3(CNT3)
29 equilibrative nucleoside transporters (ENT) SLC29A1(ENT1), SLC29A2(ENT2), SLC29A3(ENT3), SLC29A4(ENT4)
30 efflux and compartmentalization of zinc (ZNT) SLC30A1 – SLC30A10

polymorphisms in the gene encoding SLC30A8 are associated with increased diabetes risk
31 copper transporters (CTR) SLC31A1(CTR1), SLC31A2(CTR2)
these mediate uptake of dietary copper

ATP7A and ATP7B are related copper transporting P-type ATPases that mediate copper uptake and export
ATP7A is defective in Menkes disease
ATP7B is defective in Wilson disease
32 vesicular inhibitory amino acid transporter (VIAAT) SLC32A1: also called vesicular GABA transporter (VGAT)
33 acetyl-CoA transporter (ACATN) SLC33A1
34 type II Na+–phosphate co-transporters (NPT) SLC34A1: also identified as NPT2a; major transporter involved in renal phosphate reabsorption; primarily expressed in the proximal tubule
SLC34A2: also identified as NPT2b; involved in intestinal phosphate uptake from the lumen; primarily expressed in intestinal enterocytes, liver, and testis
SLC34A3: also identified as NPT2c; major transporter involved in renal phosphate reabsorption; primarily expressed in the proximal tubule
35 nucleoside sugar transporters 30 family members in humans divided into seven subfamilies identified as A through G

SLC35C1: also identified as the GDP-fucose transporter (gene symbol: FUCT1); defects in gene result in the congenital disorder of glycosylation type IIc more commonly called leukocyte adhesion deficiency syndrome II (LAD II)
36 proton–coupled amino acid transporters SLC36A1, SLC36A2, SLC36A3, SLC36A4

SLC36A1: alanine, glycine and proline transporter; also known as proton-coupled amino acid transporter 1 (PAT1); can also transport GABA
SLC36A2: glycine and proline transporter; also known as PAT2
SLC36A3: precise function unknown; also known as PAT3
SLC36A4: alanine, proline, and tryptophan transporter; also known as PAT4
37 sugar–phosphate/phosphate exchangers (SPX) SLC37A1, SLC37A2, SLC37A3, SLC37A4

SLC37A4: also known as glucose-6-phosphate transporter-1 (G6PT1) which is defective in glycogen storage disease type1b
38 sodium–coupled neutral amino acid (system N and system A) transporters (SNAT) System A family includes SLC38A1, SLC38A2, SLC38A4
SLC38A1 (SNAT1; ATA1): mediates Na+–coupled transport of neutral amino acids with preference for alanine, asparagine, cysteine, glutamine, histidine, and methionine
SLC38A4 (SNAT4; ATA3): Na+-dependent neutral amino acid transporter with braod specificity; may also transport arginine and lysine in a Na+– and pH–independent process

System N family includes SLC38A3, SLC38A5, SLC38A7
SLC38A3 (SNAT3; SN1): expressed at highest levels in the liver, pancreas, and skeletal muscle; also expressed in brain, heart, and kidney; involved in both efflux and uptake of glutamine; also transports asparagine and histidine
SLC38A5 (SNAT5: SN2): mediates Na+–coupled transport of neutral amino acids with preference for glutamine, asparagine, and histidine
SLC38A7 (SNAT7): expressed at high levels in both excitatory and inhibitory neurons and exhibits a preference for glutamine

SLC38A6 (SNAT6): an orphan member of the SLC38 family not yet fully characterized as to whether it is in the system A or N sub-family; there are 4 additional recently described orphan members SLC38A8, SLC38A9, SLC38A10, SLC38A11
39 metal ion transporters (ZIP) SLC39A1 – SLC39A14
40 basolateral iron transporter SLC40A1: more commonly known as as ferroportin, but is also known as iron-regulated gene 1 (IREG1) or reticuloendothelial iron transporter (MTP1); was also identified as SLC11A3 which is no longer used
41 MgtE–like magnesium transporters SLC41A1, SLC41A2, SLC41A3

MgtE is a divalent cation transporter first identified in the bacteria Chlamydomonas reinhardtii
42 Rh ammonia and ammonium ion transporters SLC42A1(RhAG), SLC42A2(RhBG), SLC42A3(RhCG)

these transporters are named for the Rh blood–group antigens; e.g. RhAG is encoded by the RHAG gene which is also designated as the CD241 gene (cluster of differentiation 241)
RHBG (SLC42A2): ammonia uptake from blood in kidney
RHCG (SLC42A3): ammonia uptake from blood in kidney
43 Na+–independent, system L amino acid transporters
L-type amino acid transporters, LAT
SLC43A1 (LAT3), SLC43A2 (LAT4), SLC43A3

SLC43A1: Na+-independent transport of large neutral amino acids with preferences for isoleucine, leucine, phylalanine, and valine
SLC43A2: Na+-, Cl-, and pH-independent neutral amino acid transporter; preference for isoleucine, leucine, methionine, phenylalanine, and valine
44 chlorine–like transporters SLC44A1, SLC44A2, SLC44A3, SLC44A4, SLC44A5
45 putative sugar transporters SLC45A1, SLC45A2, SLC54A3, SLC45A4
46 folate transporter family SLC46A1, SLC46A2

SLC46A1: is a H+-coupled folate transporter; also functions as a heme transporter for heme uptake in the duodenum and as such is also called heme carrier protein 1 (HCP1)
47 multidrug and toxin extrusion (MATE) SLC47A1(MATE1), SLC47A2(MATE2-K)

SLC47A1: creatine and organic anion efflux from proximal tubule cells of kidney
SLC42A2: creatine and organic anion efflux from proximal tubule cells of kidney
48 heme transporters SLC48A1 (HRG-1): essential for heme-iron recycling in reticuloendothelial macrophages during erythrophagocytosis
49 major facilitator transporters, heme transporters first family member originally identified as feline leukemia virus subgroup C cellular receptor 1 (FLVCR1)

SLC49A1 – SLC49A4
SLC49A1 (FLVCR1 is official gene symbol); protects erythroid cells from heme toxicity
SLC49A2 (FLVCR2 is official gene symbol); is a Ca2+ transporter; involved in brain vascular endothelial cell development; unlike FLVCR1-encoded protein, this protein does not bind feline leukemia virus envelope protein
50 sugar efflux transporters SLC50A1
51 steroid-derived molecule transporters SLC51A, SLC51B

SLC51A encodes organic solute transporter α-chain (OSTA, OSTα); functions as heterodimer with SLC51B; is a 7-transmembrane domain protein
SLC51B encodes organic solute transporter β-chain (OSTB, OSTβ); functions as heterodimer with SLC51A; is a single pass transmembrane protein
SLC51A:SLC51B heterodimer expressed in basolateral membranes of cells in nearly all tissues with highest levels in small intestine, liver, kidney, and steroidogenic tissues; transports bile acids, steroids, and prostaglandin E2 (PGE2); can act as efflux or uptake transporter dependent upon substrate concentration
52 riboflavin transporter family (RFVT) SLC52A1, SLC52A2, SLC52A3

mutations in SLC52A1 cause maternal riboflavin deficiency resulting in neonatal glutaric acidemia

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Clinical Significances of Transporter Defects

As might be expected, defects in the expression and/or function of membrane transporters leads to the manifestation of numerous clinical disorders. It is not the intention of this section to cover all disorders related to defects in membrane transporters but to highlight several with emphasis on diseases that have been mentioned throughout the pages of this web site or in specific disease discussion pages such as the Cystinuria page and the Hartnup disorder page.

ABCA1 is involved in the transport of cholesterol out of cells when HDLs are bound to their cell surface receptor, SR-B1 (see the Lipoproteins page for more details). One important consequence of the activity of ABCA1 in macrophages is that the efflux of cholesterol results in a suppression of inflammatory responses triggered by macrophages that have become foam cells due to cholesterol uptake. Defects in ABCA1 result in Tangier disease which is characterized by two clinical hallmarks; enlarged lipid-laden tonsils and low serum HDL.

ABCB4 is a member of the P-glycoprotein family of multidrug resistance transporters. Defects in the ABCB4 gene are associated with 6 liver diseases: progressive familial intrahepatic cholestasis type 3 (PFIC3), adult biliary cirrhosis, transient neonatal cholestasis, drug-induced cholestasis, intrahepatic cholestasis of pregnancy, and low phospholipid-associated cholelithiasis syndrome.

ABCG5 and ABCG8 form an obligate heterodimer pair that function to limit plant sterol and cholesterol uptake by the gut and mediate cholesterol efflux from the liver into the bile. Mutations in either ABCG5 or ABCG8 result in a rare genetic disorder identified as sitosterolemia (also called phytosterolemia). This disorder is characterized by unrestricted absorption of plant sterols (such as sitosterol) and cholesterol. Individuals afflicted with this disorder manifest with very high levels of plant sterols in the plasma and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease.

ABCB7 is a protein localized to the inner mitochondrial membrane and is involved in iron homeostasis. Defects in the gene are associated with X-linked sideroblastic anemia with ataxia (XSAT) which is characterized by an infantile to early childhood onset of non-progressive cerebellar ataxia and mild anemia with hypochromia and microcytosis.

ABCB11 is also known as bile salt export protein (BSEP) which is involved in bile salt transport out of hepatocytes. Defects in the gene are associated with progressive familial intrahepatic cholestasis type 2 (PFIC2).

ABCC2 was first identified as the canalicular multispecific organic anion transporter (CMOAT) and is also called multidrug resistance associated protein 2 (MRP2). Defects in the gene encoding ABCC2 result in Dubin-Johnson syndrome which is a form of conjugated hyperbilirubinemia.

ABCD1 is involved in the import and/or anchoring of very long-chain fatty acid-CoA synthetase (VLCFA-CoA synthetase) to the peroxisomes. Defects in the gene result in X-linked adrenoleukodystrophy (XALD).

ATP7A and ATP7B are copper transporting ATPases that are related to SLC31A1. Defects in ATP7A result in Menkes disease and defects in ATP7B are associated with Wilson disease.

Defects in many members of the SLC6 family are associated with mental retardation, affective disorders, and other neurological dysfunctions. SLC6A1 defects are associated with epilepsy and schizophrenia. SLC6A2 defects are associated with depression and anorexia nervosa. SLC6A3 defects are associated with Parkinsonism, Tourette syndrome, ADHD, and substance abuse. SLC6A4 defects are associated with anxiety disorder, depression , autism, and substance abuse.

SLC5A8 is a Na+-dependent transporter of short-chain fatty acids, lactate, and monocarboxylic acids. The SLC5A8 gene was originally identified as a tumor suppressor gene whose expression was silenced by hypermethylation in various colorectal carcinomas. Subsequent studies demonstrated that SLC5A8 is a major transporter of the short-chain fatty acids, in particular butyrate and propionate, produced through colonic bacterial fermentation of soluble fiber. Butyrate and propionate have been shown to be inhibitors of histone deacetylases, HDAC. Given that HDAC inhibitors are known anticancer compounds, the tumor suppressor of the SLC5A8 protein is most likely related to its role in colonic epithelial cell uptake of butyrate and propionate.

SLC6A19 is also called system B(0) neutral amino acid transporter 1 [B(0)AT1, or B0AT1]. This transporter is involved in neutral amino acid transport with highest levels of expression in the kidney and small intestine. Deficiency in SLC6A19 leads to Hartnup disorder which results from impaired transport of neutral amino acids across epithelial cells in renal proximal tubules and intestinal mucosa. Symptoms include transient manifestations of pellagra-like light sensitive rash, cerebellar ataxia, and psychosis.

SLC11A2, which is also known as DMT1 (divalent metal-ion transporter-1), is involved in the uptake of iron by the apical surface of the duodenum. In addition to iron, DMT1 is involved in manganese, cobalt, cadmium, nickel, copper, and zinc transport. Defects in DMT1 activity are associated with hypochromic microcytic anemia with iron overload.

SLC12A6 defects are associated with Andermann syndrome which is also referred to as agenesis of corpus callosum and peripheral neuropathy (ACCPN). The disorder gets its name from the fact that afflicted individuals have sensory and motor neuropathy associated

SLC16A2 is defective in Allan-Herndon-Dudley syndrome (AHDS) which is characterized by marked hypotonia, weakness, excessive drooling, reduced muscle mass, and delay of developmental milestones in infancy and early childhood. Afflicted individuals have severe impairment of cognitive development but do not exhibit any major malformations.

SLC22A18 is found in the imprinted region of chromosome 11 associated with Beckwith-Wiedemann syndrome (BWS).

SLC30A8 is involved in efflux of zinc and polymorphisms in the gene encoding this transporter are associated with increased risk of the development of type 2 diabetes. The functional defect in this protein results in impaired pancreatic β-cell function leading to defects in insulin secretion.

SLC35C1 is also known as the GDP-fucose transporter (gene symbol: FUCT1). Defects in the FUCT1 gene result in a congenital disorder of glycosylation (CDG). Specifically the disorder is a type II CDG identified as CDG-IIc. Type II CDGs result from defects in the processing of the carbohydrate structures on N-linked glycoproteins. CDG-IIc is also called leukocyte adhesion deficiency syndrome II (LAD II). LAD II is a primary immunodeficiency syndrome which manifests due to leukocyte dysfunction. Symptoms of LAD II include unique facial features (flat face with a depressed nasal bridge, antiverted nostrils, and long eyelashes), recurrent infections, persistent leukocytosis, defective neutrophil chemotaxis, and severe growth and mental retardation.

SLC40A1 is a multiple transmembrane spanning protein involved in iron transport. The protein is highly expressed in the intestine, liver, and reticuloendothelial cells. SLC40A1 is more commonly known as ferroportin or iron-regulated transporter 1 (IREG1). The protein is required for the transport of dietary iron across the basolateral membranes of intestinal enterocytes. Defects in the SLC40A1 gene are associated with type 4 hemochromatosis.

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Last modified: January 22, 2018