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Introduction to Neurotransmitters
Neurotransmitters are endogenous substances that act as chemical messengers by transmitting signals from a neuron to a target cell across a synapse. Prior to their release into the synaptic cleft, neurotransmitters are stored in secretory vesicles (called synaptic vesicles) near the plasma membrane of the axon terminal. The release of the neurotransmitter occurs most often in response to the arrival of an action potential at the synapse. When released, the neurotransmitter crosses the synaptic gap and binds to specific receptors in the membrane of the post-synaptic neuron or cell.
Neurotransmitters are generally classified into two main categories related to their overall activity, excitatory or inhibitory. Excitatory neurotransmitters exert excitatory effects on the neuron, thereby, increasing the likelihood that the neuron will fire an action potential. Major excitatory neurotransmitters include epinephrine and norepinephrine. Inhibitory neurotransmitters exert inhibitory effects on the neuron, thereby, decreasing the likelihood that the neuron will fire an action potential. Major inhibitory neurotransmitters include GABA, glycine, and serotonin. Some neurotransmitters, can exert both excitatory and inhibitory effects depending upon the type of receptors that are present.
In addition to excitation or inhibition, neurotransmitters can be broadly categorized into two groups defined as small molecule neurotransmitters or peptide neurotransmitters. Small molecule neurotransmitters include (but are not limited to) acetylcholine, GABA, and the other amino acid neurotransmitters, ATP and nitric oxide (NO). The peptide neurotransmitters include more than 50 different peptides with several being derived from the single larger protein pre-opiomelanocortin (POMC).
Table of Neurotransmitters
non-inclusive listing
| Transmitter Molecule | Derived From | Site of Synthesis |
| Acetylcholine | Choline | CNS, parasympathetic nerves |
|
Serotonin 5-Hydroxytryptamine (5-HT) |
Tryptophan | CNS, chromaffin cells of the gut, enteric cells |
| GABA | Glutamate | CNS |
| Glutamate | CNS | |
| Aspartate | CNS | |
| Glycine | spinal cord | |
| Histamine | Histidine | hypothalamus |
|
Epinephrine
synthesis pathway |
Tyrosine | adrenal medulla, some CNS cells |
|
Norpinephrine
synthesis pathway |
Tyrosine | CNS, sympathetic nerves |
|
Dopamine
synthesis pathway |
Tyrosine | CNS |
| Adenosine | ATP | CNS, peripheral nerves |
| ATP | sympathetic, sensory and enteric nerves | |
| Nitric oxide, NO | Arginine | CNS, gastrointestinal tract |
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Synaptic Transmission
Synaptic transmission refers to the propagation of nerve impulses from one nerve cell to another. This occurs at a specialized cellular structure known as the synapse, a junction at which the axon of the presynaptic neuron terminates at some location upon the postsynaptic neuron. The end of a presynaptic axon, where it is juxtaposed to the postsynaptic neuron, is enlarged and forms a structure known as the terminal button. An axon can make contact anywhere along the second neuron: on the dendrites (an axodendritic synapse), the cell body (an axosomatic synapse) or the axons (an axo-axonal synapse).
Nerve impulses are transmitted at synapses by the release of chemicals called neurotransmitters. As a nerve impulse, or action potential, reaches the end of a presynaptic axon, molecules of neurotransmitter are released into the synaptic space. The neurotransmitters are a diverse group of chemical compounds ranging from simple amines such as dopamine and amino acids such as γ-aminobutyrate (GABA), to polypeptides such as the enkephalins. The mechanisms by which they elicit responses in both presynaptic and postsynaptic neurons are as diverse as the mechanisms employed by growth factor and cytokine receptors.
back to the topNeuromuscular Transmission
A different type of nerve transmission occurs when an axon terminates on a skeletal muscle fiber, at a specialized structure called the neuromuscular junction. An action potential occurring at this site is known as neuromuscular transmission. At a neuromuscular junction, the axon subdivides into numerous terminal buttons that reside within depressions formed in the motor end-plate. The particular transmitter in use at the neuromuscular junction is acetylcholine.
back to the topNeurotransmitter Receptors
Once the molecules of neurotransmitter are released from a cell as the result of the firing of an action potential, they bind to specific receptors on the surface of the postsynaptic cell. In all cases in which these receptors have been cloned and characterized in detail, it has been shown that there are numerous subtypes of receptor for any given neurotransmitter. As well as being present on the surfaces of postsynaptic neurons, neurotransmitter receptors are found on presynaptic neurons. In general, presynaptic neuron receptors act to inhibit further release of neurotransmitter.
The vast majority of neurotransmitter receptors belong to a class of proteins known as the G-protein coupled receptors (GPCRs: see the Signal Transduction page for more information on theses receptors. The GPCRs are also called serpentine receptors because they exhibit a characteristic transmembrane structure: that is, it spans the cell membrane, not once but seven times. The link between neurotransmitters and intracellular signaling is carried out by association either with G-proteins (small GTP-binding and hydrolyzing proteins) or with protein kinases, or by the receptor itself in the form of a ligand-gated ion channel (for example, the acetylcholine receptor). One additional characteristic of neurotransmitter receptors is that they are subject to ligand-induced desensitization: That is, they can become unresponsive upon prolonged exposure to their neurotransmitter.
back to the topGlutamate: Major Excitatory Neurotransmitter
Within the CNS glutamate is the main excitatory neurotransmitter. Neurons that respond to glutamate are referred to as glutaminergic neurons. Postsynaptic glutaminergic neurons possess three distinct types of ionotropic receptors that bind glutamate released from presynaptic neurons. These ionotropic receptors have been identified on the basis of their binding affinities for certain substrates and are, thus referred to as the the kainate, 2-amino-3-hydroxy-5-methyl-4-isoxalone propionic acid (AMPA), and N-methyl-D-aspartate (NMDA) receptors. Each of these three classes of glutamate receptor subunit form ligand-gated ion channels, thus the derivation of the term ionotropic. There are multiple subtypes of each of these three classes of ionotropic glutamate receptor subunits.
The AMPA receptor subunits are referred to as GluR1 through GluR4 and each is encoded by separate genes. Functional AMPA receptors consist of heterotetramers that are formed from dimers of GluR2 and dimers of either GluR1, GluR3, or GluR4. The AMPA receptors are found on most excitatory postsynaptic neurons where they mediate fast excitation. Indeed, AMPA receptors are responsible for the bulk of fast excitatory synaptic transmission throughout the CNS. The concept of fast synaptic transmission relates to the fact that the ion channel opens and closes quickly in response to ligand (e.g. glutamate) binding. The ion permeability of the AMPA receptors is controlled by the GluR2 subunit. AMPA receptors have low permeability to calcium ions even in the ligand-activated state and this is to prevent excitotoxicity in these neurons.
The NMDA receptor subunits are identified as NMDAR1 (also called GluN1) and NMDAR2A–NMDAR2D (also called GluN2A–GluN2D). The four different NMDAR2 subunits are encoded by distinct genes. Although there is a single gene encoding the NMDAR1 subunit, multiple isoforms of this subunit are generated through alternative splicing events. The functional NMDA receptor is composed of a heterotetramer with all forms containing the NMDAR1 subunit and one of the different NMDAR2 subunits. Unlike the other ionotropic glutamate receptors, the NMDA receptors are activated by simultaneous binding of glutamate and glycine. Glycine serves as a co-agonist and both amino acid neurotransmitters must bind in order for the receptor to be activated. Glycine binds to the NMDAR1 subunit while glutamate binds to the NMDAR2 subunit. Glutamate binding to NMDA receptors results in calcium influx into the postsynaptic cells leading to the actvation of a number of signaling cascades. These signaling cascades can include activation of calcium/calmodulin-dependent kinase II (CaMKII) leading to phosphorylation of the GluA2 AMPA receptor subunit. This latter effect results in long-term potentiation (LTP). NMDAR activation also triggers PKC-dependent insertion of AMPA receptors into the synaptic membrane during LTP as well as activation of the kinases PI3K, Akt/PKB, and GSK3, each of which modulates LTP.
The kainate receptor subunits are known as GluR5 through GluR7 and KA1 and KA2. Less is known about the physiological significance of the kainate receptors. However, one important function is in the regulation of the release of the inhibitory neurotransmitter GABA (see below). This function of the kainate receptors is due to their presence on presynaptic GABAergic neurons.
Within the CNS glutaminergic neurons are responsible for the mediation of many vital processes such as the encoding of information, the formation and retrieval of memories, spatial recognition and the maintenance of consciousness. Excessive excitation of glutamate receptors has been associated with the pathophysiology of hypoxic injury, hypoglycemia, stroke and epilepsy.
Glutamate can also bind to another class of receptor termed the metabotropic glutamate receptors (mGluRs; where the small m refers to metabotropic). There are eight known metabotropic glutamate receptors identified as mGluR1–mGluR8. Unlike the ionotropic receptors, the mGluRs are members of the G-protein coupled receptor (GPCR) family. The mGluRs can be divided into three distinct subclasses based upon sequence similarities and receptor associated G-protein. Group I mGluRs include mGluR1 and mGluR5, both of which are coupled to Gq type G-proteins and upon activation trigger increased production of DAG and IP3. Group II is composed of mGluR2 and mGluR3. Group III is composed of mGluR4, mGluR6, mGluR7, and mGluR8. Both group II and III mGluRs activate an associated Gi type G-protein resulting in decreased production of cAMP. The mGluRs are primarily expressed on neurons and glial cells in close proximity to the synaptic cleft. Within the CNS, mGluRs modulate the neurotransmitter effects of glutamate as well as a variety of other neurotransmitters. In addition to the CNS, mGluRs have a widespread distribution in the periphery. Given their wide pattern of expression, diverse roles for mGluRs have been suggested. Some of these processes include control of hormone production in the adrenal gland and pancreas, regulation of mineralization in the developing cartilage, modulation of cytokine production by lymphocytes, directing the state of differentiation in embryonic stem cells, and modulation of secretory functions within the gastrointestinal tract.
Within the CNS there is an interaction between the cerebral blood flow, neurons, and the protective astrocytes that regulates the metabolism of glutamate, glutamine, and ammonia. This process is referred to as the glutamate-glutamine cycle and it is a critical metabolic process central to overall brain glutamate metabolism. Using presynaptic neurons as the starting point, the cycle begins with the release of glutamate from presynaptic secretory vesicles in response to the propagation of a nerve impulse along the axon. The release of glutamate is a Ca2+-dependent process that involves fusion of glutamate containing presynaptic vesicles with the neuronal membrane. Following release of the glutamate into the synapse it must be rapidly removed to prevent over excitation of the postsynaptic neurons. Synaptic glutamate is removed by three distinct process. It can be taken up into the postsynaptic cell, it can undergo reuptake into the presynaptic cell from which it was released or it can be taken up by a third non-neuronal cell, namely astrocytes. Postsynaptic neurons remove little glutamate from the synapse and although there is active reuptake into presynaptic neurons the latter process is less important than transport into astrocytes. The membrane potential of astrocytes is much lower than that of neuronal membranes and this favors the uptake of glutamate by the astrocyte. Glutamate uptake by astrocytes is mediated by Na+-independent and Na+-dependent systems. The Na+-dependent systems have high affinity for glutamate and are the predominant glutamate uptake mechanism in the central nervous system. There are two distinct astrocytic Na+-dependent glutamate transporters identified as EAAT1 (for Excitatory Amino Acid Transporter 1; also called GLAST) and EAAT2 (also called GLT-1).
Brain glutamate-glutamine cycle. Ammonium ion (NH4+) in the blood is taken up by astrocytes and incorporated into glutamate via glutamine synthetase. The glutamine then is transported to presynaptic neurons via SLC38A7 (also called sodium-coupled neutral amino acid transporter 7, SNAT7). Within the presynaptic neuron glutamate is formed from the glutamine via the action of glutaminase. The glutamate is packaged in secretory vesicles for release following activation of an action potential. Glutamate in the synaptic cleft can be taken up by astrocytes via the EAAT1 and EAAT2 transporters (excitatory amino acid transporters 1 and 2; also known as glial high affinity glutamte transporters). Within the astrocyter the glutamate is converted back to glutamine. Some of the astrocyte glutamine can be transported into the blood via the action of the transporter SLC38A3 (also called sodium-coupled neutral amino acid transporter 3, SNAT3).
Following uptake of glutamate, astrocytes have the ability to dispose of the amino acid via export into the blood though capillaries that contact the foot processes of the astrocytes. The problem with glutamate disposal via this mechanism is that it would eventually result in a net loss of carbon and nitrogen from the CNS. In fact, the outcome of astrocytic glutamate uptake is its conversion to glutamine. Glutamine thus serves as a "reservoir" for glutamate but in the form of a non-neuroactive compound. Release of glutamine from astrocytes allows neurons to derive glutamate from this parent compound. Astrocytes readily convert glutamate to glutamine via the glutamine synthetase catalyzed reaction as this microsomal enzyme is abundant in these cells. Indeed, histochemical data demonstrate that the glia are essentially the only cells of the CNS that carry out the glutamine synthetase reaction. The ammonia that is used to generate glutamine is derived from either the blood or from metabolic processes occurring in the brain.
Like the uptake of glutamate by astrocytes, neuronal glutamine uptake proceeds via both Na+-dependent and Na+-independent mechanisms. The major glutamine transporter in both excitatory and inhibitory neurons is the system N neutral amino acid transporter SLC38A7 (also called SNAT7). The predominant metabolic fate of the glutamine taken up by neurons is hydrolysis to glutamate and ammonia via the action of the mitochondrial enzyme, phosphate-dependent glutaminase (PAG). The inorganic phosphate (Pi) necessary for this reaction is primarily derived from the hydrolysis of ATP and its function is to lower the KM of the enzyme for glutamine. During depolarization there is a sudden increase in energy consumption. The hydrolysis of ATP to ADP and Pi thus favors the comcomitant hydrolysis of glutamine to glutamate via the resulting increased Pi. Because there is a need to replenish the ATP lost during neuronal depolarization, metabolic reactions that generate ATP must increase. It has been found that not all neuronal glutamate derived from glutamine is utilized to replenish the neurotransmitter pool. A portion of the glutamate can be oxidized within the nerve cells following transamination. The principle transamination reaction involves aspartate aminotransferase (AST) and yields α-ketoglutarate (2-oxoglutarate) which is a substrate in the TCA cycle. Glutamine, therefore, is not simply a precursor to neuronal glutamate but a potential fuel, which, like glucose, supports neuronal energy requirements.
Glutamate, released as a neurotransmitter, is taken up by astrocytes, converted to glutamine, released back to neurons where it is then converted back to glutamate represents the complete glutamate-glutamine cycle. The significance of this cycle to brain glutamate handling is that it promotes several critical processes of CNS function. Glutamate is rapidly removed from the synapse by astrocytic uptake thereby preventing over-excitation of the postsynaptic neuron. Within the astrocyte glutamate is converted to glutamine which is, in effect, a non-neuroactive compound that can be transported back to the neurons. The uptake of glutamine by neurons provides a mechanism for the regeneration of glutamate which is augmented by the generation of Pi as a result of ATP consumption during depolarization. Since the neurons also need to regenerate the lost ATP, the glutamate can serve as a carbon skeleton for oxidation in the TCA cycle. Lastly, but significantly, the incorporation of ammonia into glutamate in the astrocyte serves as a mechanism to buffer brain ammonia.
back to the topGABA
Several amino acids have distinct excitatory or inhibitory effects upon the nervous system. The amino acid derivative, γ-aminobutyrate (GABA; also called 4-aminobutyrate) is a major inhibitor of presynaptic transmission in the CNS, and also in the retina. Neurons that secrete GABA are termed GABAergic.
The formation of GABA occurs by the decarboxylation of glutamate catalyzed by glutamate decarboxylase (GAD). There are two GAD genes in humans identified as GAD1 and GAD2. The GAD isoforms produced by these two genes are identified as GAD67 (GAD1 gene: GAD67) and GAD65 (GAD2 gene: GAD65) which is reflective of their molecular weights. Both the GAD1 and GAD2 genes are expressed in the brain and GAD2 expression also occurs in the pancreas. The presence of anti-GAD antibodies (both anti-GAD65 and anti-GAD67) is a strong predictor of the future development of type 1 diabetes in high-risk populations. The activity of GAD requires pyridoxal phosphate (PLP) as a cofactor. PLP is generated from the B6 vitamins (pyridoxine, pyridoxal, and pyridoxamine) through the action of pyridoxal kinase. Pyridoxal kinase itself requires zinc for activation. A deficiency in zinc or defects in pyridoxal kinase can lead to seizure disorders, particularly in seizure-prone preeclamptic patients (hypertensive condition in late pregnancy).
GABA synthesis
GABA exerts its effects by binding to two distinct receptors, GABA-A and GABA-B. The GABA-A receptors form a Cl– channel. The binding of GABA to GABA-A receptors increases the Cl– conductance of presynaptic neurons. The anxiolytic drugs of the benzodiazepine family exert their soothing effects by potentiating the responses of GABA-A receptors to GABA binding. The GABA-B receptors are coupled to an intracellular G-protein and act by increasing conductance of an associated K+ channel.
back to the topAcetylcholine
Acetylcholine (ACh) is a simple molecule synthesized from choline and acetyl-CoA through the action of choline acetyltransferase. Neurons that synthesize and release ACh are termed cholinergic neurons. When an action potential reaches the terminal button of a presynaptic neuron a voltage-gated calcium channel is opened. The influx of calcium ions, Ca2+, stimulates the exocytosis of presynaptic vesicles containing ACh, which is thereby released into the synaptic cleft. Once released, ACh must be removed rapidly in order to allow repolarization to take place; this step, hydrolysis, is carried out by the enzyme, acetylcholinesterase. The acetylcholinesterase found at nerve endings is anchored to the plasma membrane through a glycolipid.
Synthesis of Acetylcholine
Two main classes of ACh receptors have been identified on the basis of their responsiveness to the toadstool alkaloid, muscarine, and to nicotine, respectively: the muscarinic receptors and the nicotinic receptors. The muscarinic receptors are G protein-coupled receptors (GPCR) and the nicotinic receptors are ligand-gated ion channels. Both receptor classes are abundant in the human brain. The are five subtypes of muscarinic receptors, identified as M1–M5, that are classified based upon pharmacological activity. The M1, M3, and M5 muscarinic receptors are coupled to the Gq type G-proteins that activate PLCγ. The M2 and M4 receptors are coupled to Gs type G-proteins that activate adenylate cyclase. Nicotinic receptors are divided into those found at neuromuscular junctions and those found at neuronal synapses. The activation of ACh receptors by the binding of ACh leads to an influx of Na+ into the cell and an efflux of K+, resulting in a depolarization of the postsynaptic neuron and the initiation of a new action potential. The nicotinic receptors are composed of five types of subunits which are found in different combinations in different types of nicotinic receptos. The subunits are alpha (α1–α10), beta (β2–β5), delta (δ), epsilon (ε), and gamma (γ). There are two major types of neuromuscular nicotinic receptors and five types of neuronal receptors, with one of the latter type also found in epithelial tissues.
back to the topCholinergic Agonists and Antagonists
Numerous compounds have been identified that act as either agonists or antagonists of cholinergic neurons. The principal action of cholinergic agonists is the excitation or inhibition of autonomic effector cells that are innervated by postganglionic parasympathetic neurons and as such are referred to as parasympathomimetic agents. The cholinergic agonists include choline esters (such as ACh itself) as well as protein- or alkaloid-based compounds. Several naturally occurring compounds have been shown to affect cholinergic neurons, either positively or negatively.
The responses of cholinergic neurons can also be enhanced by administration of cholinesterase (ChE) inhibitors. ChE inhibitors have been used as components of nerve gases but also have significant medical application in the treatment of disorders such as glaucoma and myasthenia gravis as well as in terminating the effects of neuromuscular blocking agents such as atropine.
back to the topNatural Cholinergic Agonist and Antagonists
| Source of Compound | Mode of Action | |
| Agonists | ||
| Nicotine | alkaloid prevalent in the tobacco plant | activates nicotinic class of ACh receptors, locks the channel open |
| Muscarine | alkaloid produced by Amanita muscaria mushrooms | activates muscarinic class of ACh receptors |
| α-Latrotoxin | protein produced by the black widow spider | induces massive ACh release, possibly by acting as a Ca2+ ionophore |
| Antagonists | ||
| atropine (and related compound Scopolamine) | alkaloid produced by the deadly nightshade, Atropa belladonna | blocks ACh actions only at muscarinic receptors |
| Botulinus toxin | eight proteins produced by Clostridium botulinum | inhibits the release of ACh |
| α-Bungarotoxin | protein produced by Bungarus genus of snakes | prevents ACh receptor channel opening |
| d-Tubocurarine | active ingredient of curare | prevents ACh receptor channel opening at motor end-plate |
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Catecholamines
The principal catecholamines are norepinephrine, epinephrine and dopamine. These compounds are formed from phenylalanine and tyrosine. Tyrosine is produced in the liver from phenylalanine through the action of phenylalanine hydroxylase. The tyrosine is then transported to catecholamine-secreting neurons where a series of reactions convert it to dopamine, to norepinephrine and finally to epinephrine (see also Specialized Products of Amino Acids).
Synthesis of the catecholamines from tyrosine
Catecholamines exhibit peripheral nervous system excitatory and inhibitory effects as well as actions in the CNS such as respiratory stimulation and an increase in psychomotor activity. The excitatory effects are exerted upon smooth muscle cells of the vessels that supply blood to the skin and mucous membranes. Cardiac function is also subject to excitatory effects, which lead to an increase in heart rate and in the force of contraction. Inhibitory effects, by contrast, are exerted upon smooth muscle cells in the wall of the gut, the bronchial tree of the lungs, and the vessels that supply blood to skeletal muscle.
In addition to their effects as neurotransmitters, norepinephrine and epinephrine can influence the rate of metabolism. This influence works both by modulating endocrine function such as insulin secretion and by increasing the rate of glycogenolysis and fatty acid mobilization.
The catecholamines bind to two different classes of receptors termed the α- and β-adrenergic receptors. The catecholamines therefore are also known as adrenergic neurotransmitters; neurons that secrete them are adrenergic neurons. Norepinephrine-secreting neurons are noradrenergic. Some of the norepinephrine released from presynaptic noradrenergic neurons is recycled in the presynaptic neuron by a reuptake mechanism.
The actions of norepinephrine and epinephrine are exerted via receptor-mediated signal transduction events. There are three distinct types of adrenergic receptors: α1, α2, β. Within each class of adrenergic receptor there are several sub-classes. The α1 class contains the α1A, α1B, and α1D receptors. The α1 receptor class are coupled to Gq-type G-proteins that activate PLCγ resulting in increases in IP3 and DAG release from membrane PIP2. The α2 class contains the α2A, α2B, and α2C receptors. The α2 class of adrenergic receptors are coupled to Gi-type G-proteins that inhibit the activation of adenylate cyclase and therefore, activation results in reductions in cAMP levels. The β class of receptors is composed of three subtypes: β1, β2, and β3 each of which couple to Gs-type G-proteins resulting in activation of adenylate cyclase and increases in cAMP with concomitant activation of PKA.
Dopamine binds to dopamineric receptors identified as D-type receptors and there are four subclasses identified as D1, D2, D4, and D5. Activation of the dopaminergic receptors results in activation of adenylate cyclase (D1 and D5) or inhibition of adenylate cyclase (D2 and D4).
Catecholamine Catabolism
Epinephrine and norepinephrine are catabolized to inactive compounds through the sequential actions of catecholamine-O-methyltransferase (COMT) and monoamine oxidase (MAO). Compounds that inhibit the action of MAO have been shown to have beneficial effects in the treatment of clinical depression, even when tricyclic antidepressants are ineffective. The utility of MAO inhibitors was discovered serendipitously when patients treated for tuberculosis with isoniazid showed signs of an improvement in mood; isoniazid was subsequently found to work by inhibiting MAO.
Metabolism of the catecholamine neurotransmitters. Only clinically important enzymes are included in this diagram. The catabolic byproducts of the catecholamines, whose levels in the cerebrospinal fluid are indicative of defects in catabolism, are in blue underlined text. Abbreviations: TH = tyrosine hydroxylase, DHPR = dihydropteridine reductase, H2B = dihydrobiopterin, H4B = tetrahydrobiopterin, MAO = monoamine oxidase, COMT = catecholamine-O-methyltransferase, MHPG = 3-methoxy-4-hydroxyphenylglycol, DOPAC = dihydroxyphenylacetic acid.
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Serotonin
Serotonin (5-hydroxytryptamine, 5HT) is formed by the hydroxylation and decarboxylation of tryptophan (see also Specialized Products of Amino Acids).
Pathway for serotonin synthesis from tryptophan. Abbreviations: THP = tryptophan hydroxylase, DHPR = dihydropteridine reductase, H2B = dihydrobiopterin, H4B = tetrahyrobiopterin, 5-HT = 5-hydroxytryptophan, AADC = aromatic L-amino acid decarboxylase.
The greatest concentration of 5HT (90%) is found in the enterochromaffin cells of the gastrointestinal tract. Most of the remainder of the body's 5HT is found in platelets and the CNS. The effects of 5HT are felt most prominently in the cardiovascular system, with additional effects in the respiratory system and the intestines. Vasoconstriction is a classic response to the administration of 5HT.
Neurons that secrete 5HT are termed serotonergic. Following the release of 5HT, a portion is taken back up by the presynaptic serotonergic neuron in a manner similar to that of the reuptake of norepinephrine.
The function of serotonin is exerted upon its interaction with specific receptors. Several serotonin receptors have been cloned and are identified as 5HT1, 5HT2, 5HT3, 5HT4, 5HT5, 5HT6, and 5HT7. Within the 5HT1 group there are subtypes 5HT1A, 5HT1B, 5HT1D, 5HT1E (a putative 5HT receptor), and 5HT1F. There are three 5HT2 subtypes, 5HT2A, 5HT2B, and 5HT2C. There are two 5HT5 subtypes, 5HT5a and 5HT5B in the human genome but the 5HT5B gene is a pseudogene. Most of these receptors are coupled to G-proteins that affect the activities of either adenylate cyclase or phospholipase Cγ. The 5HT3 class of receptors are ion channels.
| Receptor Family | Associated G-Proteins |
Result of Receptor Activation |
| 5HT1 |
Gi/Go see the Signal Transduction page for description of various G-proteins |
inhibits cAMP production, inhibitory neurotransmission |
| 5HT2 | Gq/G11 | increased production of DAG and IP3, excitatory neurotransmission |
| 5HT3 | ligand-gated Na+ and K+ channels | depolarizes axonal membrane, excitatory neurotransmission |
| 5HT4 | Gs | increases cAMP production, excitatory neurotransmission |
| 5HT5 | Gi/Go | inhibits cAMP production, inhibitory neurotransmission |
| 5HT6 | Gs | increases cAMP production, excitatory neurotransmission |
| 5HT7 | Gs | increases cAMP production, excitatory neurotransmission |
Some serotonin receptors are presynaptic and others postsynaptic. The 5HT2A receptors mediate platelet aggregation and smooth muscle contraction. The 5HT2C receptors are suspected in control of food intake as mice lacking this gene become obese from increased food intake and are also subject to fatal seizures. The 5HT3 receptors are present in the gastrointestinal tract and are related to vomiting. Also present in the gastrointestinal tract are 5HT4 receptors where they function in secretion and peristalsis. The 5HT6 and 5HT7 receptors are distributed throughout the limbic system of the brain and the 5HT6 receptors have high affinity for antidepressant drugs.
| Receptor Sub-Type | Sites of Expression | Functions |
| 5HT1A | vasculature, CNS | aggression, anxiety, blood pressure (vasoconstriction), appetite, memory, mood, cardiovascular tone, heart rate, respiration, pupillary dilation, nociception (pain sensation), sexual behavior, erectile function, emesis (vomiting), thermoregulation, sleep, addictive behaviors |
| 5HT1B | vasculature, CNS | locomotion, aggression, anxiety, blood pressure (vasoconstriction), memory, mood, learning, sexual behavior, erectile function, addictive behaviors |
| 5HT1D | vasculature, CNS | blood pressure (vasoconstriction), locomotion, anxiety |
| 5HT1F | CNS | involved in migraine headaches |
| 5HT2A | gastrointestinal tract, smooth muscles, vasculature, CNS, PNS, platelets | anxiety, blood pressure (vasoconstriction), thermoregulation, appetite, learning, memory, mood, cognitive abilities, sexual behavior, sleep, addictive behaviors |
| 5HT2B | gastrointestinal tract, smooth muscles, vasculature, CNS, PNS, platelets | gastrointestinal, motility, blood pressure (vasoconstriction), appetite, anxiety, sleep |
| 5HT2C | gastrointestinal tract, smooth muscles, vasculature, CNS, PNS, platelets | anxiety, locomotion, gastrointestinal motility, blood pressure (vasoconstriction), appetite, mood, sexual behavior, erectile function, thermoregulation, sleep, addictive behaviors |
| 5HT3 | gastrointestinal tract, CNS, PNS | anxiety, gastrointestinal motility, emesis (vomiting), learning, memory, addictive behaviors |
| 5HT4 | gastrointestinal tract, CNS, PNS | respiration, appetite, gastrointestinal motility, learning, memory, mood, anxiety |
| 5HT5A | CNS | locomotion, sleep |
| 5HT6 | CNS | cognitive abilities, learning, memory, anxiety, mood |
| 5HT7 | gastrointestinal tract, vasculature, CNS | blood pressure (vasoconstriction), respiration, thermoregulation, sleep, memory, mood, anxiety |
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Michael W King, PhD | © 1996–2013 themedicalbiochemistrypage.org, LLC | info @ themedicalbiochemistrypage.org