G protein-coupled receptors (GPCRs) are important modulators of glucose-stimulated insulin secretion, essential for maintaining energy homeostasis. Here we investigated the role of Gβ5-R7, a protein complex consisting of the atypical G protein β subunit Gβ5 and a regulator of G protein signaling of the R7 family. Using the mouse insulinoma MIN6 cell line and pancreatic islets, we investigated the effects of G protein subunit β 5 (Gnb5) knockout on insulin secretion. Consistent with previous work, Gnb5 knockout diminished insulin secretion evoked by the muscarinic cholinergic agonist Oxo-M. We found that the Gnb5 knockout also attenuated the activity of other GPCR agonists, including ADP, arginine vasopressin, glucagon-like peptide 1, and forskolin, and, surprisingly, the response to high glucose. Experiments with MIN6 cells cultured at different densities provided evidence that Gnb5 knockout eliminated the stimulatory effect of cell adhesion on Oxo-M-stimulated glucose-stimulated insulin secretion; this effect likely involved the adhesion GPCR GPR56. Gnb5 knockout did not influence cortical actin depolymerization but affected protein kinase C activity and the 14-3-3ϵ substrate. Importantly, Gnb5 -/- islets or MIN6 cells had normal total insulin content and released normal insulin amounts in response to K+-evoked membrane depolarization. These results indicate that Gβ5-R7 plays a role in the insulin secretory pathway downstream of signaling via all GPCRs and glucose. We propose that the Gβ5-R7 complex regulates a phosphorylation event participating in the vesicular trafficking pathway downstream of G protein signaling and actin depolymerization but upstream of insulin granule release.

中文翻译：

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调节性 G 蛋白信号复合物 Gβ5-R7 可促进葡萄糖和细胞外信号刺激的胰岛素分泌。

G 蛋白偶联受体 (GPCR) 是葡萄糖刺激的胰岛素分泌的重要调节剂，对于维持能量稳态至关重要。在这里，我们研究了 Gβ5-R7 的作用，Gβ5-R7 是一种蛋白质复合物，由非典型 G 蛋白 β 亚基 Gβ5 和 R7 家族 G 蛋白信号传导调节因子组成。使用小鼠胰岛素瘤 MIN6 细胞系和胰岛，我们研究了 G 蛋白亚基 β 5 (Gnb5) 敲除对胰岛素分泌的影响。与之前的研究一致，Gnb5 敲除减少了毒蕈碱胆碱能激动剂 Oxo-M 引起的胰岛素分泌。我们发现 Gnb5 敲除也减弱了其他 GPCR 激动剂的活性，包括 ADP、精氨酸加压素、胰高血糖素样肽 1 和毛喉素，以及令人惊讶的是对高葡萄糖的反应。以不同密度培养的 MIN6 细胞进行的实验提供了证据，证明 Gnb5 敲除消除了细胞粘附对 Oxo-M 刺激的葡萄糖刺激的胰岛素分泌的刺激作用；这种效应可能涉及粘附 GPCR GPR56。Gnb5 敲除不影响皮质肌动蛋白解聚，但影响蛋白激酶 C 活性和 14-3-3ϵ 底物。重要的是，Gnb5 -/- 胰岛或 MIN6 细胞具有正常的总胰岛素含量，并响应 K+ 诱发的膜去极化而释放正常的胰岛素量。这些结果表明，Gβ5-R7 在所有 GPCR 和葡萄糖信号传导下游的胰岛素分泌途径中发挥作用。