AT1R-CB₁R Heteromerization Reveals a New Mechanism for the Pathogenic Properties of Angiotensin II

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2011 May 5

PMID 21540834

Citations 77

Authors

Raphael Rozenfeld

Achla Gupta

Khatuna Gagnidze

Maribel P Lim

Ivone Gomes

Dinah Lee-Ramos

Natalia Nieto

Lakshmi A Devi

Affiliations

Soon will be listed here.

Abstract

The mechanism of G protein-coupled receptor (GPCR) signal integration is controversial. While GPCR assembly into hetero-oligomers facilitates signal integration of different receptor types, cross-talk between Gαi- and Gαq-coupled receptors is often thought to be oligomerization independent. In this study, we examined the mechanism of signal integration between the Gαi-coupled type I cannabinoid receptor (CB(1)R) and the Gαq-coupled AT1R. We find that these two receptors functionally interact, resulting in the potentiation of AT1R signalling and coupling of AT1R to multiple G proteins. Importantly, using several methods, that is, co-immunoprecipitation and resonance energy transfer assays, as well as receptor- and heteromer-selective antibodies, we show that AT1R and CB(1)R form receptor heteromers. We examined the physiological relevance of this interaction in hepatic stellate cells from ethanol-administered rats in which CB(1)R is upregulated. We found a significant upregulation of AT1R-CB(1)R heteromers and enhancement of angiotensin II-mediated signalling, as compared with cells from control animals. Moreover, blocking CB(1)R activity prevented angiotensin II-mediated mitogenic signalling and profibrogenic gene expression. These results provide a molecular basis for the pivotal role of heteromer-dependent signal integration in pathology.

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