Arrestin-biased AT1R agonism induces acute catecholamine secretion through TRPC3 coupling.
Arrestin-biased AT1R agonism induces acute catecholamine secretion through TRPC3 coupling.
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抑制蛋白偏向的 AT1R 激动作用通过 TRPC3 偶联诱导急性儿茶酚胺分泌
DOI：
10.1038/ncomms14335
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发表时间：
2017-02-09
影响因子：
16.6
通讯作者：
Sun JP
中科院分区：
文献类型：
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作者：
Liu CH;Gong Z;Liang ZL;Liu ZX;Yang F;Sun YJ;Ma ML;Wang YJ;Ji CR;Wang YH;Wang MJ;Cui FA;Lin A;Zheng WS;He DF;Qu CX;Xiao P;Liu CY;Thomsen AR;Joseph Cahill T 3rd;Kahsai AW;Yi F;Xiao KH;Xue T;Zhou Z;Yu X;Sun JP
G蛋白偶联受体（GPCR）激活引发的急性激素分泌是许多基本生理过程的基础。GPCR信号传导受到β - 抑制蛋白的负调控，β - 抑制蛋白这种衔接分子还能激活不同的细胞内信号通路。在此，我们发现TRV120027，一种血管紧张素II 1型受体（AT1R）的β - 抑制蛋白 - 1偏向性激动剂，通过与瞬时受体电位阳离子通道亚家族C成员3（TRPC3）偶联来刺激急性儿茶酚胺分泌。我们证明，TRV120027促进TRPC3或磷脂酰肌醇特异性磷脂酶C（PLCγ）募集到AT1R - β - 抑制蛋白 - 1信号复合物中。用β - 抑制蛋白 - 2的相应C末端区域替换β - 抑制蛋白 - 1的C末端区域，或使用特定的TAT - P1肽阻断β - 抑制蛋白 - 1与PLCγ之间的相互作用，会消除TRV120027诱导的TRPC3激活。综上所述，我们的结果表明，GPCR - 抑制蛋白复合物通过与离子通道偶联，在质膜上启动非脱敏性信号传导。这种快速通讯途径可能是多种细胞过程的共同机制。
血管紧张素II 1型受体（AT1R）介导的急性儿茶酚胺释放受β - 抑制蛋白调节。本文作者表明，β - 抑制蛋白 - 1将钙离子通道TRPC3和PLCγ募集到AT1R - β - 抑制蛋白复合物中，触发不依赖G蛋白的钙离子内流和儿茶酚胺分泌。
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. Angiotensin II type 1 receptor (AT1R)-mediated acute catecholamine release is modulated by β-arrestin. Here the authors show that β-arrestin-1 recruits the Ca2+ channel TRPC3 and the PLCγ to the AT1R-β-arrestin complex, triggering G protein-independent calcium influx and catecholamine secretion.