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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临界代谢作用。

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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:毒蕈碱乙酰胆碱(ACH)受体(MACHRS; M(1)-M(5))调节非凡大量重要的生理过程的活动。我们以前证明了胰腺β-细胞赋予M(3)MACRRS,其与G(Q)家族的G蛋白连接。通过ACH或其他毒蕈碱激动剂激活这些受体导致通过多种机制产生葡萄糖诱导的胰岛素释放的增强。有趣的是,在人类中,作用于人β-细胞MACHRS的ACH从相邻的α-细胞释放,所述α-细胞表达胆碱乙酰转移酶(聊天)和囊泡乙酰胆碱转运蛋白(VACHT),指示人类中非神经元胆碱能系统存在胰岛。为了阐明β-细胞M(3)受体的生理作用,我们最近产生并分析了各种突变小鼠模型。具体地,我们对胰腺β细胞中的过表达M(3)受体或突变体M(3)受体的小鼠进行了研究,或者在胰腺β-中选择性地缺乏M(3)受体或M(3) - 相关蛋白细胞。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发挥关键作用,并且旨在通过β细胞M(3)受体增强信号传导的策略可能证明改善β细胞用于治疗2型糖尿病(T2D)的功能。

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