5-HT3 receptor

The 5-HT₃ receptor belongs to the Cys-loop superfamily of ligand-gated ion channels (LGICs) and therefore differs structurally and functionally from all other 5-HT receptors (5-hydroxytryptamine, or serotonin) receptors which are G protein-coupled receptors.^[1][2][3] This ion channel is cation-selective and mediates neuronal depolarization and excitation within the central and peripheral nervous systems.^[1] As with other ligand gated ion channels, the 5-HT₃ receptor consists of five subunits arranged around a central ion conducting pore, which is permeable to sodium (Na), potassium (K), and calcium (Ca) 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 rapidly activating, desensitizing, inward current is predominantly carried by sodium and potassium ions.^[2] 5-HT₃ receptors have a negligible permeability to anions.^[1] They are most closely related by homology to the nicotinic acetylcholine receptor.

Structure

Figure 1. The mouse 5HT3 receptor as determined by X-ray crystallography. The rough position of the plasma membrane is indicated by red lines.^[4][5] A more recent study also revealed the structure by cryo-EM in vesicles.^[6]

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 composed of five identical 5-HT_3A subunits (homopentameric) or a mixture of 5-HT_3A and one of the other four 5-HT_3B,^{[7][8][9][10]} 5-HT_3C, 5-HT_3D, or 5-HT_3E subunits (heteropentameric).^[11] 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. Additionally, there has not currently been any pharmacological difference found between the heteromeric 5-HT_3AC, 5-HT_3AD, 5-HT_3AE, and the homomeric 5-HT_3A receptor.^[12]

Figure 2. The subunits are assembled as a pentamer (right) and each subunit has four transmembrane domains (left).

The subunits surround a central ion channel in a pseudo-symmetric manner (Fig.1). Each subunit comprises an extracellular N-terminal domain which comprises the orthosteric ligand-binding site; a transmembrane domain consisting of four interconnected alpha helices (M1-M4), with the extracellular M2-M3 loop involved in the gating mechanism; a large cytoplasmic domain between M3 and M4 involved in receptor trafficking and regulation; and a short extracellular C-terminus (Fig.1).^[1] Whereas extracellular domain is the site of action of agonists and competitive antagonists, the transmembrane domain contains the central ion pore, receptor gate, and principle selectivity filter that allows ions to cross the cell membrane.^[2]

Gene

The 5-HT₃ receptor gene is located on human chromosomal region 11q23.1-q23.2. It is similar in structure to the mouse gene which has 9 exons and is spread over ~13 kb. Interestingly, four of its introns are exactly in the same position as the introns in the homologous α7-Acetylcholine receptor gene, clearly proving their evolutionary relationship.^[13][14] Genes that code for the subunits of the 5-HT₃ receptor have been identified. HTR3A and HTR3B for the 5-HT_3A and 5-HT_3B subunits and in addition HTR3C, HTR3D and HTR3E genes encoding 5-HT_3C, 5-HT_3D and 5-HT_3E subunits. The latter three tend to show peripherally restricted pattern of expression, with high levels in the gut. In human duodenum and stomach, for example, 5-HT_3C and 5-HT_3E mRNA might be greater than for 5-HT_3A and 5-HT_3B. There is some evidence to suggest that the 5-HT₃ receptor subunits are an important contribution to the effectiveness of these compounds.^[2] In patients treated with chemotherapeutic drugs, certain polymorphism of the HTR3B gene could predict successful antiemetic treatment. This could indicate that the 5-HT3B receptor subunit could be used as biomarker of antiemetic drug efficacy. HTR3C and HTR3E do not seem to form functional homomeric channels, but when co-expressed with HTR3A they form heteromeric complex with decreased or increased 5-HT efficacies. The pathophysiological role for these additional subunits has yet to be identified.^[15]

Figure 3. The cDNA sequence of the mouse 5HT3 receptor. The cDNA encodes a 122 nucleotide 5' UTR and a ~510 nucleotide 3' UTR. Boxes indicate exons and the numbers below the exons indicate their length. For instance, the first exon encodes 22 amino acids plus one nucleotide belonging to a split codon with another 2 nucleotides encoded by the next exon. M1-4 indicate the transmembrane helices and C-C indicates the Cysteine loop. Modified after Uetz et al. 1994^[13]

Tissue distribution

The 5-HT₃ receptor is expressed throughout the central and peripheral nervous systems and mediates a variety of physiological functions.^[16] On a cellular level, it has been shown that postsynaptic 5-HT₃ receptors mediate fast excitatory synaptic transmission in rat neocortical interneurons, amygdala, and hippocampus, and in ferret visual cortex.^{[17][18][19][20]} 5-HT₃ receptors are also present on presynaptic nerve terminals. There is some evidence for a role in modulation of neurotransmitter release,^[21][22] but evidence is inconclusive.^[23]

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,^[24] seizure propensity ^[25]
• PNS: neuronal excitation (in autonomic, nociceptive neurons), emesis^[24]

Agonists

Agonists for the receptor include:

• 2-methyl-5-HT
• Alpha-Methyltryptamine
• Bufotenin
• Chlorophenylbiguanide^[24]
• Ethanol
• Ibogaine
• Phenylbiguanide
• Quipazine
• RS-56812: Potent and selective 5-HT₃ partial agonist, 1000x selectivity over other serotonin receptors
• SR-57227
• Varenicline^[26]
• YM-31636^[27]

Antagonists

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

• Antiemetics
  • AS-8112
  • Granisetron^[24]
  • Ondansetron
  • Tropisetron^[24]
• Gastroprokinetics
  • Alosetron
  • Batanopride
  • Metoclopramide (high doses)
  • Renzapride
  • Zacopride
  • M1, the major active metabolite of mosapride
• Antidepressants
  • Mianserin
  • Mirtazapine
  • Vortioxetine
• Antipsychotics
  • Clozapine
  • Olanzapine
  • Quetiapine
• Others
  • 3-Tropanyl indole-3-carboxylate
  • Lamotrigine (Epilepsy and Bipolar Disorder)
  • Memantine (Alzheimer's disease medication)
  • Menthol ^[28]
  • Thujone

Positive Allosteric Modulators

These agents are not agonists at the receptor, but increase the affinity or efficacy of the receptors for an agonist:

• 5-chloroindole ^[29]

Discovery

Identification of the 5-HT₃ receptor did not take place until 1986 because of a lack of selective pharmacological tool.^[16] 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^[2][30] and therefore the identification of 5-HT₃ receptors in cell lines and native tissues quickly followed.^[16]

See also

• 5-HT₁ receptor
• 5-HT₂ receptor
• 5-HT₄ receptor
• 5-HT₅ receptor
• 5-HT₆ receptor
• 5-HT₇ receptor

References

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2. Thompson AJ, Lummis SC (2006). "5-HT3 Receptors". Current Pharmaceutical Design. 12 (28): 3615–30. doi:10.2174/138161206778522029. PMC 2664614. PMID 17073663.
3. Reeves DC, Lummis SC (2002). "The molecular basis of the structure and function of the 5-HT3 receptor: a model ligand-gated ion channel (review)". Molecular Membrane Biology. 19 (1): 11–26. doi:10.1080/09687680110110048. PMID 11989819.
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5. X-ray structure of the mouse serotonin 5-HT3 receptor in PDB
6. Kudryashev M, Castaño-Díez D, Deluz C, Hassaine G, Grasso L, Graf-Meyer A, Vogel H, Stahlberg H (2015). "The Structure of the Mouse Serotonin 5-HT3 Receptor in Lipid Vesicles". Structure. doi:10.1016/j.str.2015.11.004. PMID 26724993.
7. Davies PA, Pistis M, Hanna MC, Peters JA, Lambert JJ, Hales TG, Kirkness EF (1999). "The 5-HT_3B subunit is a major determinant of serotonin-receptor function". Nature. 397 (6717): 359–63. doi:10.1038/16941. PMID 9950429.
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13. Uetz, P; Abdelatty, F; Villarroel, A; Rappold, G; Weiss, B; Koenen, M (1994). "Organisation of the murine 5-HT3 receptor gene and assignment to human chromosome 11". FEBS Letters. 339 (3): 302–6. doi:10.1016/0014-5793(94)80435-4. PMID 8112471.
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18. Kazuyoshi Kawa (1994). "Distribution and Functional Properties of 5HT₃ Receptors in the Rat Hippocampus Dentate Gyrus". Journal of Neurophysiology. 71 (5): 1935–47. PMID 7520482.
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22. Rondé P, Nichols RA (1997). "5-HT₃ receptors induce rises in cytosolic and nuclear calcium in NG108-15 cells via calcium-induced calcium release". Cell Calcium. 22 (5): 357–65. doi:10.1016/S0143-4160(97)90020-8. PMID 9448942.
23. van Hooft JA, Vijverberg HP (2000). "5-HT₃ receptors and neurotransmitter release in the CNS: a nerve ending story?". Trends Neurosci. 23 (12): 605–10. doi:10.1016/S0166-2236(00)01662-3. PMID 11137150.
24. Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. Page 187
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26. Mineur YS, Picciotto MR (December 2010). "Nicotine receptors and depression: revisiting and revising the cholinergic hypothesis". Trends Pharmacol. Sci. 31 (12): 580–6. doi:10.1016/j.tips.2010.09.004. PMC 2991594. PMID 20965579.
27. Imanishi, N.; Iwaoka, K.; Koshio, H.; Nagashima, S. Y.; Kazuta, K. I.; Ohta, M.; Sakamoto, S.; Ito, H.; Akuzawa, S.; Kiso, T.; Tsukamoto, S. I.; Mase, T. (2003). "New thiazole derivatives as potent and selective 5-hydroxytriptamine 3 (5-HT3) receptor agonists for the treatment of constipation". Bioorganic & Medicinal Chemistry. 11 (7): 1493. doi:10.1016/S0968-0896(02)00557-6.
28. Ashoor, A.; Nordman, J.; Veltri, D.; Susan Yang, K. -H.; Shuba, Y.; Al Kury, L.; Sadek, B.; Howarth, F. C.; Shehu, A.; Kabbani, N.; Oz, M. (2013). "Menthol Inhibits 5-Ht3 Receptor-Mediated Currents". Journal of Pharmacology and Experimental Therapeutics. 347 (2): 398–409. doi:10.1124/jpet.113.203976. PMID 23965380.
29. Newman, A. S.; Batis, N; Grafton, G; Caputo, F; Brady, C. A.; Lambert, J. J.; Peters, J. A.; Gordon, J; Brain, K. L.; Powell, A. D.; Barnes, N. M. (2013). "5-Chloroindole: A potent allosteric modulator of the 5-HT3 receptor". British Journal of Pharmacology. 169 (6): 1228–38. doi:10.1111/bph.12213. PMC 3831704. PMID 23594147.
30. Thompson AJ, Lummis SC (2007). "The 5-HT3 receptor as a therapeutic target". Expert Opin Ther Targets. 11 (4): 527–40. doi:10.1517/14728222.11.4.527. PMC 1994432. PMID 17373882.

External links

• 5-HT3 Receptor at the US National Library of Medicine Medical Subject Headings (MeSH)