Arrestin-biased AT1R agonism induces acute catecholamine secretion through TRPC3 coupling

Acute hormone secretion triggered by G protein-coupled receptor (GPCR) activation underlies many fundamental physiological processes. GPCR signalling is negatively regulated by beta-arrestins, adaptor molecules that also activate different intracellular signalling pathways. Here we reveal that TRV120027, a beta-arrestin-1-biased agonist of the angiotensin II receptor type 1 (AT1R), stimulates acute catecholamine secretion through coupling with the transient receptor potential cation channel subfamily C 3 (TRPC3). We show that TRV120027 promotes the recruitment of TRPC3 or phosphoinositide-specific phospholipase C (PLC gamma) to the AT1R-beta-arrestin-1 signalling complex. Replacing the C-terminal region of beta-arrestin-1 with its counterpart on beta-arrestin-2 or using a specific TAT-P1 peptide to block the interaction between beta-arrestin-1 and PLC gamma abolishes TRV120027- induced TRPC3 activation. Taken together, our results show that the GPCR-arrestin complex initiates non-desensitized signalling at the plasma membrane by coupling with ion channels. This fast communication pathway might be a common mechanism of several cellular processes.