M3-muscarinic receptor promotes insulin release via receptor phosphorylation/arrestin-dependent activation of protein kinase D1
M3-muscarinic receptor promotes insulin release via receptor phosphorylation/arrestin-dependent activation of protein kinase D1
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DOI：
10.1073/pnas.1011651107
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发表时间：
2010-12-07
影响因子：
11.1
通讯作者：
Tobin, Andrew B.
中科院分区：
文献类型：
--
作者：
Kong, Kok Choi;Butcher, Adrian J.;Tobin, Andrew B.
G蛋白偶联受体的活性是通过激动剂刺激后的过度磷酸化来调节的。尽管这一调节过程具有普遍性，但对受体磷酸化的生理影响的研究仍然很少。为了解决这个问题，我们产生了一种敲入小鼠品系，它表达M-3-M受体的磷酸化缺陷突变体，M-3-M受体是一种典型的GQ/11偶联受体。这个突变的小鼠品系被用来研究M-3-M受体磷酸化在调节胰岛胰岛素分泌中的作用。重要的是，磷酸化缺陷受体与G(Q/11)信号通路相连，但与依赖磷酸化的过程无关，如受体内化和β-arrestin募集。转基因小鼠表现出糖耐量和胰岛素分泌受损，表明胰岛上表达的M-3-M受体通过受体磷酸化/arrestin依赖的信号调节葡萄糖稳态。其机制集中在蛋白激酶D1的激活上，它在β-arrestin募集到磷酸化的M-3-M受体的下游工作。综上所述，我们的发现支持M-3-M受体介导的胰岛素持续释放增加在很大程度上独立于G蛋白偶联的独特概念，但涉及该受体与蛋白激酶D1的磷酸化/arrestin依赖的偶联。
The activity of G protein-coupled receptors is regulated via hyper-phosphorylation following agonist stimulation. Despite the universal nature of this regulatory process, the physiological impact of receptor phosphorylation remains poorly studied. To address this question, we have generated a knock-in mouse strain that expresses a phosphorylation-deficient mutant of the M-3-muscarinic receptor, a prototypical Gq/11-coupled receptor. This mutant mouse strain was used here to investigate the role of M-3-muscarinic receptor phosphorylation in the regulation of insulin secretion from pancreatic islets. Importantly, the phosphorylation deficient receptor coupled to G(q/11)-signaling pathways but was uncoupled from phosphorylation-dependent processes, such as receptor internalization and beta-arrestin recruitment. The knock-in mice showed impaired glucose tolerance and insulin secretion, indicating that M-3-muscarinic receptors expressed on pancreatic islets regulate glucose homeostasis via receptor phosphorylation-/arrestin-dependent signaling. The mechanism centers on the activation of protein kinase D1, which operates downstream of the recruitment of beta-arrestin to the phosphorylated M-3-muscarinic receptor. In conclusion, our findings support the unique concept that M-3-muscarinic receptor-mediated augmentation of sustained insulin release is largely independent of G protein-coupling but involves phosphorylation-/ arrestin-dependent coupling of the receptor to protein kinase D1.