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 β-arrestins, adaptor molecules that also activate different intracellular signalling pathways. Here we reveal that TRV120027, a β-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 (PLCγ) to the AT1R-β-arrestin-1 signalling complex. Replacing the C-terminal region of β-arrestin-1 with its counterpart on β-arrestin-2 or using a specific TAT-P1 peptide to block the interaction between β-arrestin-1 and PLCγ 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.
Liu, C-H; Gong, Z; Liang, Z-L; Liu, Z-X; Yang, F; Sun, Y-J; Ma, M-L; Wang, Y-J; Ji, C-R; Wang, Y-H; Wang, M-J; Cui, F-A; Lin, A; Zheng, W-S; He, D-F; Qu, C-X; Xiao, P; Liu, C-Y; Thomsen, ARB; Joseph Cahill, T; Kahsai, AW; Yi, F; Xiao, K-H; Xue, T; Zhou, Z; Yu, X; Sun, J-P
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