5-HT3 receptor

The 5-HT₃ receptor is a member of the superfamily of ligand-gated ion channels, a family that also includes the neuronal nicotinic acetylcholine receptors (nAChRs), and the inhibitory neurotransmitter receptors for GABA (both GABA_A and GABA_C 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.

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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.

Functional channels may be comprised 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] 5-HT_3C, 5-HT_3D, or 5-HT_3E subunits (heteropentameric).^[6] 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.^[7][8][9] 5-HT₃ receptors are also present on presynaptic nerve terminals, where they are thought to mediate or modulate neurotransmitter release.^[10][11][12]

Effects

When the receptor is activated to open the ion channel by agonists, the following effects are observed:

• CNS: anxiety^[13]
• PNS: neuronal excitation (in autonomic, nociceptive neurons), emesis^[13]

Agonists

Agonists (channel openers) for the receptor include:

• 2-methyl-5-HT
• chlorophenylbiguanide^[13]

Antagonists

Antgonists (channel closers) for the receptor (sorted by their respective therapeutic application) include:

• IBS medications
  • metoclopramide (high doses)
  • renzapride
  • alosetron
• antiemetics
  • ondansetron
  • tropisetron^[13]
  • granisetron^[13]
• mirtazapine (antidepressant)
• memantine (in Alzheimer disease)

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^[14][15] and therefore the identification of 5-HT₃ receptors in cell lines and native tissues quickly followed.^[2]

References