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

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 G alpha i- and G alpha q-coupled receptors is often thought to be oligomerization independent. In this study, we examined the mechanism of signal integration between the G alpha i-coupled type I cannabinoid receptor (CB1R) and the G alpha q-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 CB1R form receptor heteromers. We examined the physiological relevance of this interaction in hepatic stellate cells from ethanol-administered rats in which CB1R is upregulated. We found a significant upregulation of AT1R-CB1R heteromers and enhancement of angiotensin II-mediated signalling, as compared with cells from control animals. Moreover, blocking CB1R 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. The EMBO Journal (2011) 30, 2350-2363. doi: 10.1038/emboj.2011.139; Published online 3 May 2011