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

  • Nat Commun. 2017 Feb 9;8:14335. doi: 10.1038/ncomms14335.
Chun-Hua Liu  1  2  3 ,  Zheng Gong  1 ,  Zong-Lai Liang  2 ,  Zhi-Xin Liu  1 ,  Fan Yang  2 ,  Yu-Jing Sun  1 ,  Ming-Liang Ma  1 ,  Yi-Jing Wang  1 ,  Chao-Ran Ji  2 ,  Yu-Hong Wang  1 ,  Mei-Jie Wang  1 ,  Fu-Ai Cui  1 ,  Amy Lin  4 ,  Wen-Shuai Zheng  2 ,  Dong-Fang He  1  2 ,  Chang-Xiu Qu  1  2 ,  Peng Xiao  1 ,  Chuan-Yong Liu  2 ,  Alex R B Thomsen  4 ,  Thomas Joseph Cahill 3rd  4 ,  Alem W Kahsai  4 ,  Fan Yi  5 ,  Kun-Hong Xiao  4  6 ,  Tian Xue  7 ,  Zhuan Zhou  8 ,  Xiao Yu  2 ,  Jin-Peng Sun  1
Affiliations
  • 1. Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China.
  • 2. Department of Physiology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
  • 3. Department of Physiology, Taishan Medical University, Taian, Shandong 271000, China.
  • 4. Duke University, School of Medicine, Durham, North Carolina 27705, USA.
  • 5. Department of Pharmacology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
  • 6. Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
  • 7. Hefei National Laboratory for Physical Science at Microscale, School of Life Science, University of Science and Technology of China, Hefei, Anhui 230027, China.
  • 8. Laboratory of Cellular Biophysics and Neurodegeneration, Ying-Jie Conference Center, Peking University, Beijing 100871, China.
PMID: 28181498 DOI: 10.1038/ncomms14335
Abstract

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.

Products