5-HT(3) receptors

Abstract

5-Hydroxytryptamine type 3 (5-HT(3)) receptors are cation-selective Cys loop receptors found in both the central and peripheral nervous systems. There are five 5-HT(3) receptor subunits (A-E), and all functional receptors require at least one A subunit. Regions from noncontiguous parts of the subunit sequence contribute to the agonist-binding site, and the roles of a range of amino acid residues that form the binding pocket have been identified. Drugs that selectively antagonize 5-HT(3) receptors (the "setrons") are the current gold standard for treatment of chemotherapy-induced and postoperative nausea and vomiting and have potential for the treatment of a range of other conditions.

FIGURE 1.

Homology models of the 5-HT₃ receptor. A, a single receptor subunit based on the nACh receptor structure (Protein Data Bank code 2BG9) showing the mostly β-sheet-containing ECD (blue), the four transmembrane α-helices (purple), and the α-helix that forms part of the ICD (orange). The structure of the remainder of this domain is not yet known. B, models of the 5-HT₃ receptor ECD based on AChBP (blue; code 1UV6) and the nACh receptor (cyan; code 2BG9), with 5-HT docked into the intersubunit binding pocket.

FIGURE 2.

5-HT₃ receptor subunits. Shown is a Clustal alignment of representative human (h) 5-HT₃ receptor A–E subunits, demonstrating the approximate locations of the binding loops on the principal (red) and complementary (cyan) faces, the Cys-Cys loop (green), and the transmembrane α-helices (black). Note the unusual sequence construction of the D subunit, which is missing a Cys-Cys loop and parts of loops D and E and which has a region of extra sequence in the M2-M3 loop. Accession numbers are as follows: NP_000860 (A subunit), NP_006019 (B subunit), NP_570126 (C subunit), NP_001157118 (D subunit), and NP_872385 (E subunit).

FIGURE 3.

5-HT₃ receptor binding sites. Shown is a model of the 5-HT₃ receptor (with two subunits removed for clarity) showing granisetron (green) and picrotoxin (red) docked into their known binding sites in the ECD and in the pore, respectively. Other possible binding sites (pink), whose locations have not yet been confirmed, are an allosteric site in the ECD, an interhelical site in the TMD, and a lipid transmembrane site at the membrane-receptor boundary.