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.
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.|Department of Physiology, Shandong University School of Medicine, Jinan, Shandong 250012, China.|Department of Physiology, Taishan Medical University, Taian, Shandong 271000, China.
Chun-Hua
CH
Liu
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.
Zheng
Z
Gong
Department of Physiology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
Zong-Lai
ZL
Liang
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.
Zhi-Xin
ZX
Liu
Department of Physiology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
Fan
F
Yang
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.
Yu-Jing
YJ
Sun
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.
Ming-Liang
ML
Ma
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.
Yi-Jing
YJ
Wang
Department of Physiology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
Chao-Ran
CR
Ji
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.
Yu-Hong
YH
Wang
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.
Mei-Jie
MJ
Wang
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.
Fu-Ai
FA
Cui
Duke University, School of Medicine, Durham, North Carolina 27705, USA.
Amy
A
Lin
Department of Physiology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
Wen-Shuai
WS
Zheng
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.|Department of Physiology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
Dong-Fang
DF
He
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.|Department of Physiology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
Chang-Xiu
CX
Qu
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.
Peng
P
Xiao
Department of Physiology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
Chuan-Yong
CY
Liu
Duke University, School of Medicine, Durham, North Carolina 27705, USA.
Alex R B
AR
Thomsen
Duke University, School of Medicine, Durham, North Carolina 27705, USA.
Thomas
T
Joseph Cahill
Duke University, School of Medicine, Durham, North Carolina 27705, USA.
Alem W
AW
Kahsai
Department of Pharmacology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
Fan
F
Yi
Duke University, School of Medicine, Durham, North Carolina 27705, USA.|Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Kun-Hong
KH
Xiao
Hefei National Laboratory for Physical Science at Microscale, School of Life Science, University of Science and Technology of China, Hefei, Anhui 230027, China.
Tian
T
Xue
Laboratory of Cellular Biophysics and Neurodegeneration, Ying-Jie Conference Center, Peking University, Beijing 100871, China.
Zhuan
0000-0001-9048-6638
Z
Zhou
Department of Physiology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
Xiao
X
Yu
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.
Jin-Peng
JP
Sun
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism*; D004963:Estrenes / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D018345:Mice, Knockout; D009842:Oligopeptides / Q000494:pharmacology; D051966:Phospholipase C gamma / Q000378:metabolism; D011760:Pyrrolidinones / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1 / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D050052:TRPC Cation Channels / Q000378:metabolism*; D000071559:beta-Arrestin 1 / Q000737:chemistry / Q000378:metabolism*; D000071560:beta-Arrestin 2 / Q000378:metabolism*
D002395:Catecholamines; D004963:Estrenes; D008024:Ligands; D009842:Oligopeptides; D011760:Pyrrolidinones; D044140:Receptor, Angiotensin, Type 1; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D051966:Phospholipase C gamma; C555534:Sar-Arg-Val-Tyr-Ile-His-Pro-Ala-OH; D002118:Calcium