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Critical metabolic roles of β-cell M3 muscarinic acetylcholine receptors.

机译:β细胞M3毒蕈碱乙酰胆碱受体的关键代谢作用。

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Muscarinic acetylcholine (ACh) receptors (mAChRs; M(1)-M(5)) regulate the activity of an extraordinarily large number of important physiological processes. We and others previously demonstrated that pancreatic β-cells are endowed with M(3) mAChRs which are linked to G proteins of the G(q) family. The activation of these receptors by ACh or other muscarinic agonists leads to the augmentation of glucose-induced insulin release via multiple mechanisms. Interestingly, in humans, ACh acting on human β-cell mAChRs is released from adjacent α-cells which express both choline acetyltransferase (ChAT) and the vesicular acetylcholine transporter (vAChT), indicative of the presence of a non-neuronal cholinergic system in human pancreatic islets. In order to shed light on the physiological roles of β-cell M(3) receptors, we recently generated and analyzed various mutant mouse models. Specifically, we carried out studies with mice which overexpressed M(3) receptors or mutant M(3) receptors in pancreatic β-cells or which selectively lacked M(3) receptors or M(3)-receptor-associated proteins in pancreatic β-cells. Our findings indicate that β-cell M(3) receptors play a key role in maintaining proper insulin release and whole body glucose homeostasis and that strategies aimed at enhancing signaling through β-cell M(3) receptors may prove useful to improve β-cell function for the treatment of type 2 diabetes (T2D).
机译:毒蕈碱型乙酰胆碱(ACh)受体(mAChRs; M(1)-M(5))调节大量重要生理过程的活性。我们和其他人以前证明了胰腺β细胞具有M(3)mAChRs,它们与G(q)家族的G蛋白相连。 ACh或其他毒蕈碱激动剂对这些受体的激活导致通过多种机制增加葡萄糖诱导的胰岛素释放。有趣的是,在人类中,作用于人类β细胞mAChRs的ACh从表达胆碱乙酰转移酶(ChAT)和水泡乙酰胆碱转运蛋白(vAChT)的相邻α细胞中释放出来,表明人类存在非神经胆碱能系统胰岛。为了阐明β细胞M(3)受体的生理作用,我们最近生成并分析了各种突变小鼠模型。具体来说,我们对小鼠在胰腺β细胞中过表达M(3)受体或突变M(3)受体或在胰腺β-受体中选择性缺乏M(3)受体或M(3)-受体相关蛋白的小鼠进行了研究。细胞。我们的研究结果表明,β细胞M(3)受体在维持适当的胰岛素释放和全身葡萄糖稳态中起着关键作用,旨在增强通过β细胞M(3)受体的信号传导的策略可能被证明可用于改善β细胞功能用于治疗2型糖尿病(T2D)。

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