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

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.

SUBMITTER: Liu CH

PROVIDER: S-EPMC5309860 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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

Liu Chun-Hua CH Gong Zheng Z Liang Zong-Lai ZL Liu Zhi-Xin ZX Yang Fan F Sun Yu-Jing YJ Ma Ming-Liang ML Wang Yi-Jing YJ Ji Chao-Ran CR Wang Yu-Hong YH Wang Mei-Jie MJ Cui Fu-Ai FA Lin Amy A Zheng Wen-Shuai WS He Dong-Fang DF Qu Chang-Xiu CX Xiao Peng P Liu Chuan-Yong CY Thomsen Alex R B AR Joseph Cahill Thomas T Kahsai Alem W AW Yi Fan F Xiao Kun-Hong KH Xue Tian T Zhou Zhuan Z Yu Xiao X Sun Jin-Peng JP

Nature communications 20170209

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 ...[more]

PMID: 28181498

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Project description:RationaleMicroRNAs (miRs) are small, non-coding RNAs that function to post-transcriptionally regulate target genes. First transcribed as primary miR transcripts (pri-miRs), they are enzymatically processed by Drosha into premature miRs (pre-miRs) and further cleaved by Dicer into mature miRs. Initially discovered to desensitize β-adrenergic receptor (βAR) signaling, β-arrestins are now well-appreciated to modulate multiple pathways independent of G protein signaling, a concept known as biased signaling. Using the β-arrestin-biased βAR ligand carvedilol, we previously showed that β-arrestin1 (not β-arrestin2)-biased β1AR (not β2AR) cardioprotective signaling stimulates Drosha-mediated processing of six miRs by forming a multi-protein nuclear complex, which includes β-arrestin1, the Drosha microprocessor complex and a single-stranded RNA binding protein hnRNPA1.ObjectiveHere, we investigate whether β-arrestin-mediated βAR signaling induced by carvedilol could regulate Dicer-mediated miR maturation in the cytoplasm and whether this novel mechanism promotes cardioprotective signaling.Methods and resultsIn mouse hearts, carvedilol indeed upregulates three mature miRs, but not their pre-miRs and pri-miRs, in a β-arrestin 1- or 2-dependent manner. Interestingly, carvedilol-mediated activation of miR-466g or miR-532-5p, and miR-674 is dependent on β2ARs and β1ARs, respectively. Mechanistically, β-arrestin 1 or 2 regulates maturation of three newly identified βAR/β-arrestin-responsive miRs (β-miRs) by associating with the Dicer maturation RNase III enzyme on three pre-miRs of β-miRs. Myocardial cell approaches uncover that despite their distinct roles in different cell types, β-miRs act as gatekeepers of cardiac cell functions by repressing deleterious targets.ConclusionsOur findings indicate a novel role for βAR-mediated β-arrestin signaling activated by carvedilol in Dicer-mediated miR maturation, which may be linked to its protective mechanisms.

Dataset Information

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

Publications

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

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