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

作者：Liu, Chun-Hua; Gong, Zheng; Liang, Zong-Lai; Liu, Zhi-Xin; Yang, Fan; Sun, Yu-Jing; Ma, Ming-Liang; Wang, Yi-Jing; Ji, Chao-Ran; Wang, Yu-Hong; Wang, Mei-Jie; Cui, Fu-Ai; Lin, Amy; Zheng, Wen-Shuai; He, Dong-Fang; Qu, Chang-xiu; Xiao, Peng; Liu, Chuan-Yong; Thomsen, Alex R. B.; Cahill, Thomas Joseph, III; Kahsai, Alem W.; Yi, Fan; Xiao, Kun-Hong; Xue, Tian; Zhou, Zhuan; Yu, Xiao; Sun, Jin-Peng^*

来源：Nature Communications, 2017, 8(1): 14335.

DOI：10.1038/ncomms14335

• STRESS-RESPONSE PATHWAY
• INSULIN-SECRETION
• CHROMAFFIN CELLS
• HEART-FAILURE
• RECEPTOR
• ACTIVATION
• BETA-ARRESTIN-1
• INHIBITION
• CALMODULIN
• CHANNELS

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.

• 出版日期2017-2-9
• 单位山东大学; 山东第一医科大学; 中国科学技术大学; 北京大学