5-HT3 receptor
Encyclopedia
The 5-HT3 receptor is a member of the superfamily of ligand-gated ion channel
s, a superfamily that also includes the neuronal nicotinic acetylcholine receptor
s (nAChRs), and the inhibitory neurotransmitter receptors for GABA
(both GABAA
and GABAA-ρ receptors) and glycine
. The 5-HT3 receptor is most closely related by homology to the nicotinic acetylcholine receptor.
The 5-HT3 receptor consists of 5 subunits arranged around a central ion conducting pore, which is permeable to sodium, potassium, and calcium ions. Binding of the neurotransmitter
5-hydroxytryptamine (serotonin
) to the 5-HT3 receptor opens the channel, which, in turn, leads to an excitatory response in neurons. The 5-HT3 receptor differs markedly in structure and mechanism from the other 5-HT receptor
subtypes, which are all G-protein-coupled.
A functional channel may be compossed of five identical 5-HT3A
subunits (homopentameric) or a mixture of 5-HT3A and one of the other four 5-HT3B, 5-HT3C, 5-HT3D, or 5-HT3E subunits (heteropentameric). It appears that only the 5-HT3A subunits form functional homopentameric channels. All other subunit subtypes must heteropentamerize with 5-HT3A subunits to form functional channels.
and peripheral nervous system
s and mediates a variety of physiological functions. On a cellular level, it has been shown that postsynaptic 5-HT3 receptors mediate fast excitatory synaptic transmission in rat neocortical interneurons and amygdala
, and in ferret visual cortex
. 5-HT3 receptors are also present on presynaptic nerve terminals, where they are thought to mediate or modulate neurotransmitter release.
- and radiotherapy-induced vomiting
, and the concomitant development of selective 5-HT3 receptor antagonist
s to suppress these side effects aroused intense interest from the pharmaceutical industry and therefore the identification of 5-HT3 receptors in cell lines and native tissues quickly followed.
Ligand-gated ion channel
Ligand-gated ion channels are one type of ionotropic receptor or channel-linked receptor. They are a group of transmembrane ion channels that are opened or closed in response to the binding of a chemical messenger , such as a neurotransmitter.The binding site of endogenous ligands on LGICs...
s, a superfamily that also includes the neuronal nicotinic acetylcholine receptor
Nicotinic acetylcholine receptor
Nicotinic acetylcholine receptors, or nAChRs, are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction...
s (nAChRs), and the inhibitory neurotransmitter receptors for GABA
Gamma-aminobutyric acid
γ-Aminobutyric acid is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system...
(both GABAA
GABA A receptor
The GABAA receptor is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid , the major inhibitory neurotransmitter in the central nervous system. Upon activation, the GABAA receptor selectively conducts Cl- through its pore, resulting in...
and GABAA-ρ receptors) and glycine
Glycine receptor
The glycine receptor, or GlyR, is the receptor for the amino acid neurotransmitter glycine. GlyR is an ionotropic receptor that produces its effects through chloride current...
. The 5-HT3 receptor is most closely related by homology to the nicotinic acetylcholine receptor.
The 5-HT3 receptor consists of 5 subunits arranged around a central ion conducting pore, which is permeable to sodium, potassium, and calcium ions. Binding of the neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
5-hydroxytryptamine (serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
) to the 5-HT3 receptor opens the channel, which, in turn, leads to an excitatory response in neurons. The 5-HT3 receptor differs markedly in structure and mechanism from the other 5-HT receptor
5-HT receptor
The serotonin receptors, also known as 5-hydroxytryptamine receptors or 5-HT receptors, are a group of G protein-coupled receptors and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory neurotransmission...
subtypes, which are all G-protein-coupled.
Structure
As with other ligand gated ion channels, the 5-HT3 receptor is composed of five subunits pseudo symmetrically arranged about a central ion conducting pore. These subunits are proteins encoded by the , , , , and/or genes.A functional channel may be compossed of five identical 5-HT3A
HTR3A
5-hydroxytryptamine receptor 3A is a protein that in humans is encoded by the HTR3A gene....
subunits (homopentameric) or a mixture of 5-HT3A and one of the other four 5-HT3B, 5-HT3C, 5-HT3D, or 5-HT3E subunits (heteropentameric). It appears that only the 5-HT3A subunits form functional homopentameric channels. All other subunit subtypes must heteropentamerize with 5-HT3A subunits to form functional channels.
Tissue distribution
The 5-HT3 receptor is expressed throughout the centralCentral nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
and peripheral nervous system
Peripheral nervous system
The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
s and mediates a variety of physiological functions. On a cellular level, it has been shown that postsynaptic 5-HT3 receptors mediate fast excitatory synaptic transmission in rat neocortical interneurons and amygdala
Amygdala
The ' are almond-shaped groups of nuclei located deep within the medial temporal lobes of the brain in complex vertebrates, including humans. Shown in research to perform a primary role in the processing and memory of emotional reactions, the amygdalae are considered part of the limbic system.-...
, and in ferret visual cortex
Visual cortex
The visual cortex of the brain is the part of the cerebral cortex responsible for processing visual information. It is located in the occipital lobe, in the back of the brain....
. 5-HT3 receptors are also present on presynaptic nerve terminals, where they are thought to mediate or modulate neurotransmitter release.
Effects
When the receptor is activated to open the ion channel by agonists, the following effects are observed:- CNSCentral nervous systemThe central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
: nausea and vomiting center in brain stemBrain stemIn vertebrate anatomy the brainstem is the posterior part of the brain, adjoining and structurally continuous with the spinal cord. The brain stem provides the main motor and sensory innervation to the face and neck via the cranial nerves...
, anxiety, seizure propensity - PNSPeripheral nervous systemThe peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
: neuronal excitation (in autonomic, nociceptive neurons), emesis
Agonists
Agonists for the receptor include:- 2-methyl-5-HT
- varenicline
- ChlorophenylbiguanideChlorophenylbiguanideChlorophenylbiguanide Chlorophenylbiguanide Chlorophenylbiguanide (1-(3-Chlorophenylbiguanide, m-CPBG) is a selective agonist for the 5HT3 receptor. It has anxiogenic, emetic and hypothermic effects in animal studies....
- QuipazineQuipazineQuipazine is a piperazine drug used in scientific research. It is a moderately selective serotonin receptor antagonist, binding to a range of different serotonin receptors, but particularly to the 5-HT2A and 5-HT3....
- RS-56812RS-56812RS-56812 is a potent and selective partial agonist at the 5HT3 receptor. It has been shown to improve performance on animal tests of memory....
: potent and selective 5-HT3 partial agonist, 1000x selectivity over other serotonin receptors - SR-57227
- YM-31636
Antagonists
Antagonists for the receptor (sorted by their respective therapeutic application) include:- AntiemeticAntiemeticAn antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer....
s- AS-8112AS-8112AS-8112 is a synthetic compound that acts as a selective antagonist at the dopamine receptor subtypes D2 and D3, and the serotonin receptor 5-HT3. It has potent antiemetic effects in animal studies and has been investigated for potential medical use....
- GranisetronGranisetronGranisetron is a serotonin 5-HT3 receptor antagonist used as an antiemetic to treat nausea and vomiting following chemotherapy. Its main effect is to reduce the activity of the vagus nerve, which is a nerve that activates the vomiting center in the medulla oblongata. It does not have much effect...
- OndansetronOndansetronOndansetron is a serotonin 5-HT3 receptor antagonist used mainly as an antiemetic , often following chemotherapy. Its effects are thought to be on both peripheral and central nerves...
- TropisetronTropisetronTropisetron is a serotonin 5-HT3 receptor antagonist used mainly as an antiemetic to treat nausea and vomiting following chemotherapy, although it has been used experimentally as an analgesic in cases of fibromyalgia. The drug is available in a 5 mg oral preparation or in 2 mg...
- AS-8112
- Gastroprokinetics
- AlosetronAlosetronAlosetron is a 5-HT3 antagonist used for the management of severe diarrhea-predominant irritable bowel syndrome in women only. It is currently marketed by Prometheus Laboratories Inc...
- BatanoprideBatanoprideBatanopride is an antiemetic drug of the benzamide class which acts as a selective 5-HT3 receptor antagonist. It was trialled to reduce nausea during cancer chemotherapy, but was never approved for medical use due to dose-limiting side effects including hypotension and long QT syndrome....
- MetoclopramideMetoclopramideMetoclopramide is an antiemetic and gastroprokinetic agent. It is commonly used to treat nausea and vomiting, to facilitate gastric emptying in people with gastroparesis, and as a treatment for the gastric stasis often associated with migraine headaches.-Medical uses:Metoclopramide is commonly...
(high doses) - RenzaprideRenzaprideRenzapride is a gastroprokinetic agent and antiemetic which acts as a full 5-HT4 full agonist and 5-HT3 antagonist. It also functions as a 5-HT2B antagonist and has some affinity for the 5-HT2A and 5-HT2C receptors, though it is unlikely that these properties contribute to its therapeutic...
- ZacoprideZacoprideZacopride is a potent antagonist at the 5HT3 receptor and an agonist at the 5HT4 receptor. It has anxiolytic and nootropic effects in animal models, with the enantiomer being the more active form...
- Alosetron
- AntidepressantAntidepressantAn antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
s- MianserinMianserinMianserin is a psychoactive drug of the tetracyclic antidepressant chemical class which is classified as a noradrenergic and specific serotonergic antidepressant and has antidepressant, anxiolytic, hypnotic, antiemetic, orexigenic, and antihistamine effects...
- MirtazapineMirtazapineMirtazapine is a tetracyclic antidepressant used primarily in the treatment of depression. It is also sometimes used as a hypnotic, antiemetic, and appetite stimulant, and for the treatment of anxiety, among other indications...
- Mianserin
- AntipsychoticAntipsychoticAn antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...
s- ClozapineClozapineClozapine is an antipsychotic medication used in the treatment of schizophrenia, and is also used off-label in the treatment of bipolar disorder. Wyatt. R and Chew...
- OlanzapineOlanzapineOlanzapine is an atypical antipsychotic, approved by the FDA for the treatment of schizophrenia and bipolar disorder...
- QuetiapineQuetiapineQuetiapine , is an atypical antipsychotic approved for the treatment of schizophrenia, and bipolar disorder....
- Clozapine
- Others
- Memantine (Alzheimer's diseaseAlzheimer's diseaseAlzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
medication)
- Memantine (Alzheimer's disease
Discovery
Identification of the 5-HT3 receptor did not take place until 1986 because of a lack of selective pharmacological tool. However, with the discovery that the 5-HT3 receptor plays a prominent role in chemotherapyChemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
- and radiotherapy-induced vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
, and the concomitant development of selective 5-HT3 receptor antagonist
5-HT3 antagonist
The 5-HT3 antagonists are a class of medications that act as receptor antagonists at the 5-HT3 receptor, a subtype of serotonin receptor found in terminals of the vagus nerve and in certain areas of the brain....
s to suppress these side effects aroused intense interest from the pharmaceutical industry and therefore the identification of 5-HT3 receptors in cell lines and native tissues quickly followed.