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 GABA_A and GABA_A-ρ receptors) and glycine.^[1][2] 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 HTR3A, HTR3B, HTR3C, HTR3D, and/or HTR3E genes.

A functional channel may be compossed of five identical 5-HT_3A subunits (homopentameric) or a mixture of 5-HT_3A and one of the other four 5-HT_3B,^[3][4][5][6] 5-HT_3C, 5-HT_3D, or 5-HT_3E subunits (heteropentameric).^[7] It appears that only the 5-HT_3A subunits form functional homopentameric channels. All other subunit subtypes must heteropentamerize with 5-HT_3A 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.^[2] 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.^[8][9][10] 5-HT₃ receptors are also present on presynaptic nerve terminals, where they are thought to mediate or modulate neurotransmitter release.^[11][12][13]

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,^[14] seizure propensity ^[15]
• PNS: neuronal excitation (in autonomic, nociceptive neurons), emesis^[14]

Agonists

Agonists for the receptor include:

• 2-methyl-5-HT
• Alpha-Methyltryptamine
• varenicline^[16]
• Chlorophenylbiguanide^[14]
• Quipazine
• RS-56812: potent and selective 5-HT₃ partial agonist, 1000x selectivity over other serotonin receptors
• SR-57227
• YM-31636^[17]

Antagonists

Antagonists for the receptor (sorted by their respective therapeutic application) include:

• Antiemetics
  • AS-8112
  • Granisetron^[14]
  • Ondansetron
  • Tropisetron^[14]
• 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.^[2] 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^[18][19] and therefore the identification of 5-HT₃ receptors in cell lines and native tissues quickly followed.^[2]

References

External links

• MeSH 5-HT3+Receptor