Effects of mutations at conserved TM II residues on ligand binding and activation of mouse 5-HT6 receptor

European Journal of Pharmacology
Jiaping ZhangRichard Z Chen

Abstract

An aspartate residue (Asp-72) in the transmembrane helix II of mouse 5-hydroxytryptamine-6 receptor (5-HT6) is conserved among most G protein-coupled receptors. We have examined the functional significance of this residue by site-directed mutagenesis. A single Asp --> Ala (D72A) mutation resulted in an 8-fold decrease in apparent affinity for 5-HT, and a 60-fold reduction in EC50 value of agonist-induced stimulation of adenylyl cyclase. A F69L/T70I/D72A triple mutant showed a 2-fold reduction in apparent affinity for 5-HT but complete loss of adenylyl cyclase stimulation. Binding of SB-258585 (4-iodo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzene-sulfonamide), a selective 5-HT6 antagonist, was mildly affected (2- to 4-fold decrease in affinity) in the two mutants. Our data suggest that Asp-72 and additional residues toward the intracellular side of TM II have a limited role in ligand binding but are critical for functional activation of the 5-HT6 receptor.

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Citations

Jun 2, 2014·Nature Chemical Biology·Fanny DuhrSéverine Chaumont-Dubel
Aug 30, 2008·Brain Research·Andrea FrassettoRichard Z Chen
Feb 13, 2020·Science Signaling·Camille N PujolSéverine Chaumont-Dubel
Oct 24, 2018·Journal of Medicinal Chemistry·Márton VassChris de Graaf

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