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.
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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. 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 are referred to as flipases.
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).back to the top
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) forms the surface of vesicles involved in the transfer of proteins between successive Golgi compartments. 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.
Tight junctions are primarily found in the epithelia and are designed for occlusion. Tight junctions act as barriers that regulate the movement of solutes and water between various epithelial layers. 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.
Adherens junctions are composed of transmembrane proteins that serve to anchor cells via interactions with the extracellular matrix. The proteins of adherens junctions are members of the various cadherin and integrin protein families. 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).
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.back to the top
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.
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 over 15 different K+-specific voltage-regulated 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 11 aquaporin proteins have been identified in mammals with 10 known in humans (termed AQP0 through AQP9). A related family of proteins is called the aquaglyceroporins which are involved in water transport as well as the transport of other small molecules. AQP9 is the human aquaglyceroporin. 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, and AQP8, while the collecting ducts express AQP2, AQP3, AQP4, AQP6, and AQP8. Loss of function of the renal aquaporins is associated with several disease states. Reduced expression of AQP2 is associated with nephrogenic diabetes insipidus (NDI), acquired hypokalemia, and hypercalcemia.
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.
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.
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.back to the top
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 they are autophosphorylated by ATP during the transport process. There are four different types of ATPases 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.
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 leasst 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.
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.
|ATPase Family||Function||Member Names / Comments|
|1||Na+/K+ transporters||the ATP1A genes all encode the catalytic α-subunit, while the ATP1B genes all encode the regulatory glycoprotein β-subunit
ATP1A1, ATP1A2, ATP1A3, ATP1A4, ATP1B1, ATP1B2, ATP1B3, ATP1B4
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 containin 1, SNW1 (also known as SKI-interacting protein, SKIP)
|2||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 transporters
|4||H+/K+ transporters||ATP4A: encodes the α-subunit of the stomach parietal cell H+ transporter
ATP4B: encodes the β-subunit of the stomach parietal cell H+ transporter
|5||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 of mitochondrial F0 complex
ATP5S: encodes the s-subunit (factor B) of mitochondrial F0 complex
|6||H+ transporters, lysosomal||
ATP6AP1 and ATP6AP2 encode vacuolar (V-type) ATPase accessory proteins
ATP6AP2 encoded protein 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
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
ATP8B1, ATP8B2, and ATP8B3: involved in phosphatidylserine (PS) and phosphatidylethanolamine (PE) transport from one side of a membrane to the other
ATP8B4: phospholipid transporter
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
|11||metal transporters||ATP11A, ATP11B, ATP11C|
|12||H+/K+ transporters, non-gastric||ATP12A: encodes the catalytic subunit of ouabain-sensitive H+/K+-ATPases|
|13||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
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 and three β-subunit genes in humans. The α1 isoform is the predominant form and is 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.
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 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.back to the top
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 through ABCG. Each member of a given subfamily is distinguished with numbers (e.g. ABCA1). The ABCA subfamily comprises 12 genes, the ABCB subfamily comprises 11 genes, the ABCC subfamily comprises 12 genes, the ABCD subfamily comprises 4 genes, the ABCE subfamily comprises 1 gene, the ABCF subfamily comprises 3 genes, and the ABCG subfamily comprises 5 genes. In order to keep the size of the following Table limited, only those ABC transporters (of the 48 expressed genes) whose functions have been defined or assessed by in vitro assays are included.
|Gene Symbol||Other Names||Chromosome||Functions/Comments|
|ABCA1||ABC1||9q31.1||transfer of cellular cholesterol and phospholipids to HDLs (reverse cholesterol transport); defects in gene associated with development of Tangier disease|
|ABCA2||ABC2||9q34||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||1p22.1–p22||expressed exclusively in retinal photoreceptors; in association with the process of phtotransduction 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|
|ABCB1||PGY1, MDR1||7p21.1||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||6p21.3||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||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||77q21.1||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|
|ABCB6||MTABC3||1q42||mitochondrial transporter involved in heme biosynthesis; transports porphyrins into mitochondria|
|ABCB7||ABC7||Xq12–q13||transport of heme from mitochondria to the cytosol; iron-sulfur (Fe/S) cluster transport|
|ABCB11||BSEP, SPGP||2q24||BSEP: bile salt export protein, bile salt transport out of hepatocytes, gene defects associated with progressive familial intrahepatic cholestasis type 2 (PFIC2)|
|ABCC1||MRP1||16p13.1||MRP1: multidrug resistance associated protein 1; 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||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, CMOAT3||17q21.3||MRP3: multidrug resistance associated protein 3; CMOAT3: canalicular multispecific organic anion transporter; involved in drug resistance|
|ABCC4||MRP4, MOATB||13q32||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||MRP5: multidrug resistance associated protein 5; MOATB: multispecific organic anion transporter C; resistance to thiopurines and antiretroviral nucleoside analogs|
|ABCC6||MRP6, PXE||16p13.1||MRP6: multidrug resistance associated protein 6; PXE: pseudoxanthoma elasticum, a rare disorder in which the skin, eyes, heart, and other soft tissues become calcified|
|CFTR||ABCC7||7q31.2||CFTR: cystic fibrosis transmembrane conductance regulator; chloride ion channel; gene defects result in cyctic fibrosis|
|ABCC8||SUR||11p15.1||SUR: sulfonylurea receptor; target of the type 2 diabetes drugs such as glipizide|
|ABCD1||ALD||Xq28||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||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||70kDa peroxisomal membrane protein; also called peroxisomal membrane protein 1; mutation associated with Zellweger syndrome 2 (ZWS2)|
|ABCD4||PMP69, P70R, PXMP1L||14q24.3||related to the other ABCD family members but localized to ER membranes; also called peroxisomal membrane protein 1-like; mutations increase severity of XALD|
|ABCE1||OABP, RNS4I||4q31||OABP: oligoadenylate binding protein; RNS4I: ribonuclease 4 inhibitor|
|ABCG1||ABC8, White1||21q22.3||involved in mobilization and efflux of intracellular cholesterol; responsible for approximately 20% of cholesterol efflux to HDLs (reverse cholesterol transport)|
|ABCG2||ABCP, MXR, BCRP||4q22||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 porphyrin export; is also a major uric acid secretion transporter in the small intestine|
|ABCG4||White2||11q23.3||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||White3||2p21||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|
|ABCG8||Sterolin 2||2p21||see above for ABCG5|
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||Member Names / Comments|
|1||high affinity glutamate and neutral amino acid transporters||
SLC1A – SLC1A7
SLC1A1 is also called excitatory amino acid transporter 3 (EAAT3)
SLC1A2 is called EAAT2; decreased expression of SLC1A2 is associated with amyotrophic lateral sclerosis (ALS: Lou Gehrig disease)
SLC1A4 and SLC1A5 are the neutral amino acid transporters
|2||facilitative GLUT transporters||
SLC2A1 – SLC2A14
SLC2A1 is GLUT1; this glucose transporter is 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)
Defects in the SLCA1 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; this glucose transporter is found primarily in neurons and possess the lowest Km for glucose of any of the glucose transporters
SLC2A4 is GLUT4; this glucose transporter is expressed predominantly in insulin-responsive tissues such as skeletal muscle and adipose tissue
SLC2A5 is GLUT5 is the major 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
SLC2A9 (GLUT9; also known as URATv1) is a major uric acid transporter in the liver and kidneys
SLC2A10 is GLUT10; glucoase and galactose transporter
SLC2A11 is GLUT11; glucose and fructose transporter
SLC2A12 is GLUT12; glucose transporter
SCL2A13 is also called the proton (H+) myo–inositol cotransporter, HMIT
heavy subunits of heteromeric amino acid transport
activator of dibasic and neutral amino acid transport
SLC3A1 is the gene encoding one of the subunits (rBAT) of the renal cystine transporter necessary
for cystine reabsorption by the proximal tubules of the kidney and can be defective in
SLC3A2 [also known as 4F2 which forms heterodimers with light chain subunits LAT1:SLC7A5, y(+)LAT1:SCL7A7, and y(+)LAT2:SLC7A6]
|4||sodium bicarbonate transporters (NBC)||
SLC4A1 (BND3), SLC4A2, SLC4A3, SLC4A4 (NBC1), SLC4A5, SLC4A7 (mNBC3), SLC4A8
(kNBC3), SLC4A9, SLC4A10, SLC4A11
SLC4A1 is also known as BND3 (band 3 of red cell membranes); mutations in SLC4A1 associated with inherited renal tubular acidosis (both autosomal recessive and autosomal dominant forms)
SLC4A4 (NBC1) mutations associated with renal proximal tubular acidosis
SLC4A7 (mNBC3 and NBC2 variant) was formerly identified as SLC4A6 and so the SLC4A6 identity is no longer used
SLC4A11 is a Na+-borate co-transporter; mutations associated with corneal endothelial dystrophy
|5||sodium glucose co–transporters (SGLT)||
SLC5A1 – SLC5A12
SLC5A1 is commonly called SGLT1 which is a Na+-dependent intestinal glucose and galactose transporter
SLC5A2 is 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
SLC5A3 is a Na+-myoinositol glucose co-transporter (SMIT)
SLC5A4 is also known as the Na+-dependent amino acid transporter 1 (SAAT1)
SLC5A5 is a Na+-iodide co-transporter commonly identified as NIS; mutations associated with thyroid dyshormonogenesis
SLC5A6 is a Na+-dependent pantothenate, biotin, and lipoic acid transporter; also identified as Na+-multivitamin transporter (SMVT)
SLC5A8 is a lactate, monocarboxylate, and short-chain fatty acid transporter also known as Na+-monocarboxylate transporter 1 (SMCT1)
SLC5A9 is SGLT4 which is a glucose and mannose transporter
SLC5A10 is SGLT5
SLC5A11 is SGLT6 which is a myo-inositol glucose transporter
SLC5A12 is a lactate transporter also known as the Na+-monocarboxylate transporter 2 (SMCT2)
|6||sodium– and chloride–dependent neurotransmitter transporters||
SLC6A1 – SLC6A20
SLC6A1, SLC6A11, SLC6A12, and SLC6A13 are GABA transporters in GABAergic neurons and elsewhere in the brain
SLC6A2 is a major norepinephrine transporter in the brain and in adrenal medulary chromaffin cells
SLC6A3 is a 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
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
SLC6A19 is involved in neutral amino acid transport, deficiency results in Hartnup disorder; protein also called system B0 neutral amino acid transporter 1 (B0AT1)
|7||cationic amino acid transporters [y(+) system] and the glycoprotein-associated amino acid transporters||
SLC7A1 – SLC7A11, SLC7A13, SLC7A14
SLC7A5 is also called L-type amino acid transporter 1, LAT1
SLC7A6 is also called y(+)L-type amino acid transporter 2, y(+)LAT2
SLC7A7 is also called y(+)L-type amino acid transporter 1, y(+)LAT1
SLC7A8 is also called L-type amino acid transporter 2, LAT2
LAT1, y(+)LAT1, and y(+)LAT2 are the light chains of the heterodimeric cell surface antigen 4F2 (4F2 is also SLC3A2)
SLC7A9 is the gene encoding one of the subunits [b(0,+)AT] of the renal cystine transporter responsible for cystine reabsorption in the proximal tubules of the kidney and can be defective in cystinurias
|8||K+-dependent Na+/Ca2+ exchangers (NCK proteins)||
SLC8A1, SLC8A2, SLC8A3, SLC8B1
SLC8B1 formerly identified as SLC24A6
|9||Na+/H+ exchangers||SLC9A1 – SLC9A9|
|10||sodium bile salt co-transporters||
SLC10A1, SLC10A2, SLC10A3, SLC10A4, SLC10A5, SLC10A6, SLC10A7
SLC10A1: also called NTCP for Na+-taurocholate cotransporting polypeptide, NTCP is involved in hepatic uptake of bile acids through the sinusoidal/basolateral membrane
SLC10A3, SLC10A4, and SLC10A5 are considered orphan transporters
|11||proton-coupled metal ion transporters||
SLC11A1, SLC11A2, SLC11A3
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-transporter||SLC12A1 – SLC12A9|
|13||Na+–sulfate/carboxylate co-transporters||SLC13A1, SLC13A2, SLC13A3, SLC13A4, SLC13A5|
SLC14A1 (UT-B): erythrocyte urea transporter; UT-B1 and UT-B2 isoforms
SLC14A2 (UT-A): renal Na+-independent urea transporter; UT-A1 to UT-A6 isoforms
|15||proton oligopeptide co-transporters||
SLC15A1, SLC15A2, SLC15A3, SLC15A4
SLC15A1 and SLC15A2 transport di- and tripeptides (but not free amino acids) from small intestine into enterocytes
SLC15A3 and SLC15A4 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 are plasma membrane lactate and ketone body transporters
SCL16A1 also transports pyruvate but only across the plasma membrane
SLC16A9 is a lactate transporter
SLC16A10 (TAT1: T-type amino acid transporter) is a Na+-independent aromatic amino acid transporter
|17||organic anion transporters; originally identified as type I Na+–phosphate co-transporters||
SLC17A1 – SLC17A9
SLC17A6, SLC17A7, and SCL17A8 are glutamate transporters in the brain; SLC17A8 also transports glutamate in the liver and kidney
|18||vesicular amine transporters||SLC18A1, SLC18A2, SLC18A3|
|19||folate/thiamine transporters||SLC19A1, SLC19A2, SLC19A3|
|20||type III Na+–phosphate co-transporters||
also called Pit-1 and Pit-2 (Pi=inorganic phosphate, t=transporter)
|organic anion transporting polypeptides (OATP)||there are at least 11 human SLCO family members divided into 6 subfamilies identified as 1 through 6; these transporters have the nomenclature SLCO followed by the family number, subfamily letter, and member number; e.g. SLCO1B1 is a sinusoidal/basolateral membrane Na+-independent transporter, also called the organic anion transporting polypeptide 1B1 (OATP1B1). SLCO1B1 was formerly identified as OATPC and also as SLC21A6.|
|22||organic cation transporters (OCTs), zwitterion/cation transporters (OCTNs) and organic anion transporters (OATs)||
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
|23||Na+–dependent vitamin C cotransporters (SVCT)||
SLC23A1, SLC23A2, SLC23A3
SLC23A1 (SVCT1) found in intestinal and renal epithelial cells where it is responsible for ascorbic acid uptake from the diet and re-absorption within the kidneys, respectively
SLC23A2 (SVCT2) present in the plasma membrane of all nucleated cells, responsible for ascorbate uptae from the blood
SLC23A3 and SLC23A4 are orphan transporters
|24||Na+/(Ca2+–K+) exchangers (NCKX proteins)||
SLC24A1 – SLC24A5 (NCKX1 – NCKX5)
SLC24A1 (NCKX1) is expressed in platelets and rod photoreceptors; mutations cause congenital stationary night blindness
SLC24A4 (NCKX4) is involved in skin, hair, and eye pimentation
SLC24A5 (NCKX5) is involved in skin, hair, and eye pimentation; mutations are associated with oculotaneous albinism type VI
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
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
SLC26A1 is a hepatic, renal, and intestinal sulfate and oxalate transporter
SLC26A2 is a chloride and sulfate transporter which is mutated in diastrophic dysplasia (DTD) which is associated with undersulfation of proteoglycans in cartilage matrices
SLC26A4 is also called pendrin, expressed at significant levels only in the thyroid gland where it is involved in iodine homeostasis and thyroid hormone biosynthesis; also functions in chloride and bicarbonate transport in 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 is chloride and bicarbonate transporter in kidney tubule, intestines, and pancreas
SLC26A7 is a chloride, sulfate, and bicarbonate transporter in gastric parietal cells
SLC26A9 is a chloride and bicarbonate transporter in gastric parietal cells, airway epithelial cells, and kidney
SLC26A10 is a pseudogene
|27||fatty acid transporters (FATPs)||
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)
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)
FATP3 is also known as acyl-CoA synthetase very long-chain family, member 3 (ACSVL3)
FATP4 is also known as acyl-CoA synthetase very long-chain family, member 4 (ACSVL4)
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)
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)
FATP function is discussed in the Fatty Acid Oxidation page
|28||Na+–dependent concentrative nucleoside transport (CNTs)||SLC28A1, SLC28A2, SLC28A3|
|29||equilibrative nucleoside transporters (ENTs)||SLC29A1, SLC29A2, SLC29A3, SLC29A4|
|30||efflux and compartmentalization of zinc (ZNTs)||
SLC30A1 – SLC30A10
polymorphisms in the gene encoding SLC30A8 are associated with increased diabetes risk
|31||copper transporters (CTRs)||
these mediate copper uptake
ATP7A and ATP7B are related copper transporting P-type ATPases that mediate copper uptake and export
ATP7A is defective in Menkes disease and ATP7B is defective in Wilson disease
|32||vesicular inhibitory amino acid transporter (VIAAT)||SLC32A1 is also called vesicular GABA transporter (VGAT)|
|33||acetyl-CoA transporter (ACATN)||SLC33A1|
|34||type II Na+–phosphate co-transporters||SLC34A1, SLC34A2, SLC34A3|
|35||nucleoside sugar transporters||
30 family members in humans divided into
seven subfamilies identified as A through G
SLC35C1 is 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|
|37||sugar–phosphate/phosphate exchangers (SPXs)||
SLC37A1, SLC37A2, SLC37A3, SLC37A4
SLC37A4 is 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/A) transporters (SNATs)||
System A family includes
SLC38A1, SLC38A2, SLC38A4
SLC38A1 (SNAT1; ATA1) mediates Na+–coupled transport of neutral amino acids with preference for glutamine, asparagine, and histidine
SLC38A2 (SNAT2; ATA2)
SLC38A4 (SNAT4; ATA3) is Na+– and pH– independent for transport of cationic amino acids and dependent on both for transport of neutral amino acids
System N family includes SLC38A3, SLC38A5, SLC38A7
SLC38A3 (SNAT3; SN1) is 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
SLC38A5 (SNAT5: SN2) mediates Na+–coupled transport of neutral amino acids with preference for glutamine, asparagine, and histidine
SLC38A7 (SNAT7) is expressed at high levels in both excitatory and inhibitory neurons and exhibits a preference for glutamine
SLC38A6 (SNAT6) is 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 (ZIPs)||SLC39A1 – SLC39A14|
|40||basolateral iron transporter||SLC40A1 is 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 ammonium transporters||
SLC42A1, SLC42A2, SLC42A3
also identified as RhAG, RhBG, 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)
Na+–independent, system L amino acid transporters
L-type amino acid transporters, LAT
|SLC43A1 (LAT3), SLC43A2 (LAT4), SLC43A3|
|44||chlorine–like transporters||SLC44A1, SLC44A2, SLC44A3, SLC44A4, SLC44A5|
|45||putative sugar transporters||SLC45A1, SLC45A2, SLC54A3, SLC45A4|
|46||folate transporter family||
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)||
excretion of endogenous and exogenous toxic electrolytes via bile and urine
SLC48A1 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 encodes organic solute transporter α-chain (OSTA, OSTα); intestinal bile transporter
SLC51B encodes organic solute transporter β-chain (OSTB, OSTβ)
|52||riboflavin transporter family (RFVT)||
SLC52A1, SLC52A2, SLC52A3
mutations in SLC52A1 cause maternal riboflavin deficiency resulting in neonatal glutaric acidemia
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.
As the name implies, cystinuria is a disorder associated with excess cystine in the urine. Cystine is the oxidized disulfide homodimer of two cysteines. Cystinuria is an autosomal recessive disorder that results from a failure of the renal proximal tubules to reabsorb cystine that was filtered by the glomerulus. The disorder results from defects in either of the two protein subunits of the cystine transporter which is distinct from the renal cysteine transporter. In addition to excess cystine in the urine, the disorder is also associated with increased urinary excretion of dibasic amino acids arginine, lysine, and ornithine. However, clinical consequences are only associated with the increased urinary cystine and is due to the poor solubility of this homodimeric compound. Cystine will precipitate in the urine resulting in the formation of renal calculi (stones) that can lead to renal failure. The two subunits of the cystine transporter are encoded by the SLC3A1 and SLC7A9 genes that encode the basic amino acid transport protein (rBAT) and the functional subunit that transports neutral and basic amino acids (b(0,+)AT; where the AT stands for amino acid transporter), respectively.
Common treatments for patients with cystinuria are to decrease protein and salt intake as well as to ensure increased hydration as this will dilute the cystine in the urine reducing the potential for crystal formation. In addition, patients are given drugs, such as acetazolamide (a carbonic anhydrase inhibitor principally utilized in the treatment of glaucoma and certain forms of hypertension), which alkalizes the urine thereby reducing the potential for urinary precipitation of cystine. In addition, thiol drugs can be used to compete for the formation of cystine. These drugs include captopril [an angiotensin converting enzyme (ACE) inhibitor used principally in the treatment of hypertension], D-penicillamine (a chelator drug used in the treatment of Wilson disease, lead poisoning, and rheumatoid arthritis), and alpha-mercaptopropionylglycine, α-MPG (a second-generation chelating drug).back to the top
Hartnup disorder was first described in 1956 in the Hartnup family in London as a renal aminoaciduria of neutral amino acids associated with a pellagra-like skin rash and episodes of cerebellar ataxia. The disorder is caused by a defect in neutral amino acid transport in the apical brush border membranes of the small intestine and in kidney proximal tubules. The transporter is a member of the solute carrier family, specifically the SLC6A19 transporter. SLC6A19 is also known as the system B(0) neutral amino acid transporter 1 [B(0)AT1]. SLC6A19 is responsible for the transport of neutral amino acids in a Na+-dependent transport reaction. The lack of intestinal tryptophan transport is responsible for most, if not all, clinical phenotypes of Hartnup disorder. The pellagra-like skin rash seen on sun-exposed areas of skin in Hartnup disorder patients is most likely the result of nicotinamide deficiency due to a lack of tryptophan which is a precursor for its synthesis. Symptoms of Hartnup disorder may begin in infancy or early childhood, but sometimes they begin as late as early adulthood. Symptoms may be triggered by sunlight, fever, drugs, or emotional or physical stress. Most symptoms occur sporadically and are caused by a deficiency of niacin. When Hartnup disorder manifests during infancy the symptoms can be variable in clinical presentation. These symptoms include failure to thrive, photosensitivity, intermittent ataxia, nystagmus and tremor. Patients with Hartnup disorder can remain asymptomatic on a high protein diet due to intestinal peptide absorption via the actions of the transporter, PepT1.back to the top
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).
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.
SLC6A19 is also called system B(0) neutral amino acid transporter 1 [B(0)AT1]. 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 with agenesis of the corpus callosum. The incidence of this disorder is high in French Canadians living in the Charlevoix region of Quebec.
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 CDGIIc. Type II CDGs result from defects in the processing of the carbohydrate structures on N-linked glycoproteins. CDGIIc 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, 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 insulin-regulated gene 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.back to the top