PubMed 23077719

Referenced in Channelpedia wiki pages of: none

Automatically associated channels: Kir2.3 , TRP

Title: A Coupled Array of Noncovalent Interactions Impacts the Function of the 5-HT(3)A Serotonin Receptor in an Agonist-Specific Way.

Authors: Timothy F Miles, Kiowa S Bower, Henry A Lester, Dennis A Dougherty

Journal, date & volume: ACS Chem Neurosci, 2012 Oct 17 , 3, 753-60

PubMed link:

The serotonin type 3A (5-HT(3)A) receptor is a Cys-loop (pentameric) neurotransmitter-gated ion channel found in the central and peripheral nervous systems and implicated in numerous diseases. In previous studies with the endogenous agonist serotonin, we identified two interactions critical for receptor function: a cation-π interaction with W183 in loop B (TrpB) and a hydrogen bond to E129 in loop A. Here we employ mutant cycle analyses utilizing conventional and unnatural amino acid mutagenesis to demonstrate that a third residue, D124 of loop A, forms two functionally important hydrogen bonds to the backbone of loop B. We also show that these three interactions, the cation-π interaction, the backbone hydrogen bonds, and the E129 hydrogen bond, are tightly coupled to each other, suggesting they function as a single unit. We also identify key functional differences between serotonin and the competitive partial agonist m-chlorophenyl biguanide (mCPBG) at these residues. mCPBG displays no cation-π at TrpB and extreme sensitivity to the positioning of E129, on which it is reliant for initiation of channel gating.