Regulator of G-protein signaling Gβ5-R7 is a crucial activator of muscarinic M3 receptor-stimulated insulin secretion.
Regulator of G-protein signaling Gβ5-R7 is a crucial activator of muscarinic M3 receptor-stimulated insulin secretion.
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G 蛋白信号传导调节剂Gβ5-R7 是毒蕈碱M3 受体刺激胰岛素分泌的重要激活剂。
DOI：
10.1096/fj.201700197rr
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发表时间：
2017
期刊：
影响因子：
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通讯作者：
Slepak,VladlenZ
中科院分区：
文献类型：
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作者：
Wang,Qiang;Pronin,AlexeyN;Levay,Konstantin;Almaca,Joana;Fornoni,Alessia;Caicedo,Alejandro;Slepak,VladlenZ
在胰腺 β 细胞中，毒蕈碱胆碱能受体 M3 (M3R) 刺激葡萄糖诱导的胰岛素分泌。 G 蛋白信号调节蛋白 (RGS) 是 GPCR 活性的关键调节蛋白，但它们在 β 细胞中的作用仍然很大程度上未知。 R7 亚家族 RGS 蛋白由 G 蛋白亚基 Gβ5 稳定，因此 Gnb5 基因的敲除会导致所有 R7 亚基降解。我们发现小鼠或分泌胰岛素的 MIN6 细胞系中的 Gnb5 敲除几乎完全消除了 M3R 的促胰岛素活性。此外，Gβ5-RGS7 的过度表达强烈促进 M3R 刺激的胰岛素分泌。对 Gnb5−/− MIN6 细胞中这种非典型机制的检查表明，cAMP、二酰基甘油或 Ca2+ 水平没有受到显着影响。 Gnb5−/− 小鼠胰岛中游离 Ca2+ 反应的幅度没有降低，但胆碱能激动剂诱导的 Ca2+ 振荡频率降低了 30% 以上。 Gnb5 的消融会损害 M3R 刺激的 ERK1/2 磷酸化。表皮生长因子对 Gnb5−/− 细胞中 ERK 通路的刺激使 M3R 刺激的胰岛素释放恢复到接近正常水平。鉴定 Gβ5-R7 在胰岛素分泌中的新作用可能会带来改善胰腺 β 细胞功能的新治疗方法。—Wang, Q.、Pronin, A. N.、Levay, K.、Almaca, J.、Fornoni, A.、Caicedo, A.、Slepak, V. Z. G 蛋白信号传导调节剂 Gβ5-R7 是毒蕈碱 M3 受体刺激的胰岛素分泌的关键激活剂。
In pancreatic β cells, muscarinic cholinergic receptor M3 (M3R) stimulates glucose-induced secretion of insulin. Regulator of G-protein signaling (RGS) proteins are critical modulators of GPCR activity, yet their role in β cells remains largely unknown. R7 subfamily RGS proteins are stabilized by the G-protein subunit Gβ5, such that the knockout of the Gnb5 gene results in degradation of all R7 subunits. We found that Gnb5 knockout in mice or in the insulin-secreting MIN6 cell line almost completely eliminates insulinotropic activity of M3R. Moreover, overexpression of Gβ5-RGS7 strongly promotes M3R-stimulated insulin secretion. Examination of this noncanonical mechanism in Gnb5−/− MIN6 cells showed that cAMP, diacylglycerol, or Ca2+ levels were not significantly affected. There was no reduction in the amplitude of free Ca2+ responses in islets from the Gnb5−/− mice, but the frequency of Ca2+ oscillations induced by cholinergic agonist was lowered by more than 30%. Ablation of Gnb5 impaired M3R-stimulated phosphorylation of ERK1/2. Stimulation of the ERK pathway in Gnb5−/− cells by epidermal growth factor restored M3R-stimulated insulin release to near normal levels. Identification of the novel role of Gβ5-R7 in insulin secretion may lead to a new therapeutic approach for improving pancreatic β-cell function.—Wang, Q., Pronin, A. N., Levay, K., Almaca, J., Fornoni, A., Caicedo, A., Slepak, V. Z. Regulator of G-protein signaling Gβ5-R7 is a crucial activator of muscarinic M3 receptor-stimulated insulin secretion.