title: AT1R-CB₁R heteromerization reveals a new mechanism for the pathogenic properties of angiotensin II.
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.
authors.affiliation: Department of Pharmacology and Systems Therapeutics, New York Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Raphael
authors.initials: R
authors.lastname: Rozenfeld
authors.forename: Achla
authors.initials: A
authors.lastname: Gupta
authors.forename: Khatuna
authors.initials: K
authors.lastname: Gagnidze
authors.forename: Maribel P
authors.initials: MP
authors.lastname: Lim
authors.forename: Ivone
authors.initials: I
authors.lastname: Gomes
authors.forename: Dinah
authors.initials: D
authors.lastname: Lee-Ramos
authors.forename: Natalia
authors.initials: N
authors.lastname: Nieto
authors.forename: Lakshmi A
authors.initials: LA
authors.lastname: Devi
mesh_terms: D000804:Angiotensin II / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002450:Cell Communication / Q000235:genetics; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D020239:Receptor Cross-Talk / Q000502:physiology; D044140:Receptor, Angiotensin, Type 1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D043884:Receptor, Cannabinoid, CB1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D008024:Ligands; D044140:Receptor, Angiotensin, Type 1; D043884:Receptor, Cannabinoid, CB1; D000804:Angiotensin II; D048049:Extracellular Signal-Regulated MAP Kinases