5-HT3 receptor

The 5-HT3 receptor is a member of the superfamily of ligand-gated ion channels, a superfamily that also includes the neuronal nicotinic acetylcholine receptors (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.

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 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 central and peripheral nervous systems 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.

Effects
When the receptor is activated to open the ion channel by agonists, the following effects are observed:
 * CNS: nausea and vomiting center in brain stem, anxiety, seizure propensity
 * PNS: neuronal excitation (in autonomic, nociceptive neurons), emesis

Agonists
Agonists for the receptor include:
 * 2-methyl-5-HT
 * varenicline
 * Chlorophenylbiguanide
 * Quipazine
 * RS-56812: 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:
 * Antiemetics
 * AS-8112
 * Granisetron
 * Ondansetron
 * Tropisetron
 * Gastroprokinetics
 * Alosetron
 * Batanopride
 * Metoclopramide (high doses)
 * Renzapride
 * Zacopride
 * Antidepressants
 * Mianserin
 * Mirtazapine
 * Antipsychotics
 * Clozapine
 * Olanzapine
 * Quetiapine
 * Others
 * Memantine (Alzheimer's disease medication)

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 chemotherapy- and radiotherapy-induced vomiting, and the concomitant development of selective 5-HT3 receptor antagonists 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.