5-IP7 is a GPCR messenger mediating neural control of synaptotagmin-dependent insulin exocytosis and glucose homeostasis
5-IP7 is a GPCR messenger mediating neural control of synaptotagmin-dependent insulin exocytosis and glucose homeostasis
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5-IP7 是一种 GPCR 信使，介导突触结合蛋白依赖性胰岛素胞吐作用和葡萄糖稳态的神经控制
DOI：
10.1038/s42255-021-00468-7
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发表时间：
2021-10
影响因子：
20.8
通讯作者：
C
中科院分区：
文献类型：
--
作者：
Xiaozhe Zhang;Na Li;Jun Zhang;Yanshen Zhang;Xiaoli Yang;Yifan Luo;Bobo Zhang;Zhixue Xu;Zhenhua Zhu;Xiuyan Yang;Yuan Yan;Biao Lin;Shen Wang;Da Chen;Cai-Chao Ye;Yan Ding;Mingliang Lou;Qingcui Wu;Zhanfeng Hou;Keren Zhang;Ziming Liang;Anqi Wei;Bianbian Wang;C
5-二磷酸肌醇五磷酸（5-IP7）是与各种细胞过程相关的信号代谢物。细胞外刺激如何引起5-IP7信号转导尚不清楚。在这里，我们发现β细胞中的5-IP7介导突触结合蛋白-7（Syt 7）依赖性胰岛素释放的副交感神经刺激。机制上，迷走神经刺激和毒蕈碱乙酰胆碱受体的激活触发Gαq-PLC-PKC-PKD依赖性信号传导并激活IP 6 K1，即5-IP7合酶。尽管5-IP7及其前体IP 6都与PIP 2竞争结合Syt 7，但Ca 2+以高亲和力选择性结合5-IP7，释放Syt 7以使含胰岛素的囊泡与细胞膜融合。β细胞特异性IP 6 K1缺失减少了由毒蕈碱刺激引起的胰岛素分泌和葡萄糖清除，而携带磷酸化模拟、过度活跃的IP 6 K1突变体的小鼠显示出增加的胰岛素释放、先天性高胰岛素血症和肥胖。这些表型在缺乏Syt 7的小鼠中不存在。我们的研究为肌醇焦磷酸生理学提出了一个新的概念框架，其中5-IP7在外周神经系统和代谢器官之间的界面处充当GPCR第二信使，传递Gq偶联的GPCR刺激以解除Syt 7依赖性以及其他胞吐事件。
5-diphosphoinositol pentakisphosphate (5-IP7) is a signalling metabolite linked to various cellular processes. How extracellular stimuli elicit 5-IP7 signalling remains unclear. Here we show that 5-IP7 in β cells mediates parasympathetic stimulation of synaptotagmin-7 (Syt7)-dependent insulin release. Mechanistically, vagal stimulation and activation of muscarinic acetylcholine receptors triggers Gαq-PLC-PKC-PKD-dependent signalling and activates IP6K1, the 5-IP7 synthase. Whereas both 5-IP7 and its precursor IP6 compete with PIP2 for binding to Syt7, Ca2+ selectively binds 5-IP7 with high affinity, freeing Syt7 to enable fusion of insulin-containing vesicles with the cell membrane. β-cell-specific IP6K1 deletion diminishes insulin secretion and glucose clearance elicited by muscarinic stimulation, whereas mice carrying a phosphorylation-mimicking, hyperactive IP6K1 mutant display augmented insulin release, congenital hyperinsulinaemia and obesity. These phenotypes are absent in mice lacking Syt7. Our study proposes a new conceptual framework for inositol pyrophosphate physiology in which 5-IP7 acts as a GPCR second messenger at the interface between peripheral nervous system and metabolic organs, transmitting Gq-coupled GPCR stimulation to unclamp Syt7-dependent, and perhaps other, exocytotic events.
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影响因子：
7
作者：
MATTHEWS, DR;CLARK, A
通讯作者：
CLARK, A
影响因子：
64.5
作者：
Chakraborty A;Koldobskiy MA;Bello NT;Maxwell M;Potter JJ;Juluri KR;Maag D;Kim S;Huang AS;Dailey MJ;Saleh M;Snowman AM;Moran TH;Mezey E;Snyder SH
通讯作者：
Snyder SH
影响因子：
4.8
作者：
Rajasekaran SS;Kim J;Gaboardi GC;Gromada J;Shears SB;Dos Santos KT;Nolasco EL;Ferreira SS;Illies C;Köhler M;Gu C;Ryu SH;Martins JO;Darè E;Barker CJ;Berggren PO
通讯作者：
Berggren PO
影响因子：
7.3
作者：
Chakraborty A;Kim S;Snyder SH
通讯作者：
Snyder SH
影响因子：
2.2
作者：
Tamarina NA;Roe MW;Philipson L
通讯作者：
Philipson L