AT1R-CB₁R heteromerization reveals a new mechanism for the pathogenic properties of angiotensin II

EMBO J. 2011 May 3;30(12):2350-63. doi: 10.1038/emboj.2011.139.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Angiotensin II / chemistry*
  • Angiotensin II / genetics
  • Angiotensin II / metabolism*
  • Animals
  • Cell Communication / genetics
  • Cell Line, Tumor
  • Extracellular Signal-Regulated MAP Kinases / chemistry
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • HEK293 Cells
  • Humans
  • Ligands
  • MAP Kinase Signaling System / genetics
  • Mice
  • Mice, Inbred BALB C
  • Rats
  • Receptor Cross-Talk / physiology
  • Receptor, Angiotensin, Type 1 / chemistry*
  • Receptor, Angiotensin, Type 1 / genetics
  • Receptor, Angiotensin, Type 1 / metabolism*
  • Receptor, Cannabinoid, CB1 / chemistry*
  • Receptor, Cannabinoid, CB1 / genetics
  • Receptor, Cannabinoid, CB1 / metabolism*

Substances

  • Ligands
  • Receptor, Angiotensin, Type 1
  • Receptor, Cannabinoid, CB1
  • Angiotensin II
  • Extracellular Signal-Regulated MAP Kinases