5-hydroxytryptamine receptor: Difference between revisions

<scene name='71/716548/5-ht3_receptor/1'>The 5-HT3 receptor</scene> is a pentameric cation-selective ion channel and plays a role in neuronal excitation to release neurotransmitters from the postsynaptic neuron. Opening of the cation channel causes an influx of sodium and calcium through the receptor pore leading to a membrane depolarization. Five receptor subunits, A to E, have been found in humans but only subunits A and B have been found in rodents. When experimentally expressed in a host, the 5-HT3 receptor is comprised of either A or AB subunits which can result in a homopentameric receptor or a heteropentameric receptor respectively. The A and B subunits are found throughout the brain in areas such as the hippocampus and amygdala. 5-HT3 is a transmembrane channel that is stimulated to open state by the interaction of the receptor with serotonin in the extracellular space.<ref>Hassaine G,Cedric D, Luigino G, Romain W, Menno BT, Ruud H, Alexandra G, Henning S, Takashi T, Aline D, Christophe M, Xiao-Dan L, Frederic P, Horst V, Hugues N. ''X-ray Structure of the Mouse Serotonin 5-HT3 Receptor. Nature 512.7514 (2014): 276-81.[http://www.nature.com/nature/journal/v512/n7514/full/nature13552.html DOI:10.1038/nature13552]</ref> The binding site is comprised of six loops from two adjacent subunits in the extracellular N-terminal domain. Loops A, B and C form the principal subunit and contain the <scene name='71/716548/5-ht3/1'>important side chains</scene> N128, W183 and Y234. Loops D, E and F form the complementary subunit of the binding site and contain the important side chains W90, Y143 and W195. The transmembrane region is comprised of multiple alpha helical structures and mediates ion flow and ion specificity.<ref name = two> Thompson AJ, Lummis SCR. 5-HT3 Receptors. Curr Pharm Des. 2006; 12(28): 3615–3630. PMID:2664614 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2664614/]</ref>

5-HT3 antagonists have been predominantly used as an antiemetic drug in relieving treating symptoms such as nausea and vomiting for a cancer patient receiving chemotherapy. Three high affinity antagonist often used are granisetron, tropisteron and ondansetron. The common structure shared among 5-HT3 antagonists contains an amine with an aromatic ring system and a carbonyl group. <ref name = "two" /> Experimental homology modeling suggests that 5-HT3 antagonists have aromatic rings that form π-π interactions with the tyrosine, Y143 and tryptophan, W183, side chains of the 5-HT3 receptor. It is also theorized that the antagonist contain carbonyl groups which accept hydrogen bonds from serine, S227, side chain of the 5-HT3 receptor.<ref>Maksay G, Zsolt B, Miklós S. ''Binding Interactions of Antagonists with 5‐Hydroxytryptamine 3A Receptor Models.'' Journal of Receptors and Signal Transduction 23.2-3 (2003): 255-70. [http://www.tandfonline.com/doi/full/10.1081/RRS-120025568 DOI:10.1081/RRS-120025568]</ref> During the binding of granisteron to the 5-HT3 receptor, the aromatic rings sit within W183 and Y234 and an azabicyclic ring within W90 and F226 of the binding pocket.<ref name = "two" /> Once a 5-HT3 antagonist has bound to a 5-HT3 receptor, serotonin binding is inhibited.<ref>Brunton LL, Lazo JS, Parker KL. (2006). Goddman & Gilman's The Pharmacological Basis of Therapeutics. New York: McGraw-Hill. pp. 1000–3. ISBN 978-0-07-142280-2.</ref>