AT1R-CB₁ R 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 ±i- and G ±q-coupled receptors is often thought to be oligomerization independent. In this study, we examined the mechanism of signal integration between the G ±i-coupled type I cannabinoid receptor (CB 1 R) and the G ±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 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.