Constitutively Active Mutants of 5-HT4 Receptors Are They in Unique Active States?

Overview

Journal EMBO Rep

Specialty Molecular Biology

Date 2001 Mar 17

PMID 11252726

Citations 5

Authors

S Claeysen

M Sebben

C Becamel

M L Parmentier

A Dumuis

J Bockaert

Affiliations

Soon will be listed here.

Abstract

Somatic mutations leading to constitutively active G-protein coupled receptors (GPCRs) are responsible for certain human diseases. A consistent structural description of the molecular change underlying the conversion of GPCRs from an inactive R state to an active R* state is lacking. Here, we show that a series of constitutively active 5-HT4 receptors (mutated or truncated in the C-terminal and the third intracellular loop) were characterized by an increase in their denaturation rate at 55 degrees C. The thermal denaturation kinetics were monophasic, suggesting that we were measuring mainly the denaturation rate of R*. Analysis of these kinetics revealed that constitutively active C-terminal domain mutants, were due to a change in the J constant governing the R/R* equilibrium. However, the constitutive activity of the receptor mutated within the third intracellular loop was the result of both a change in the allosteric J constant and a change in the R* conformation.

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