학술논문
5-IP7 is a GPCR messenger mediating neural control of synaptotagmin-dependent insulin exocytosis and glucose homeostasis
Document Type
Original Paper
Author
Zhang, Xiaozhe; Li, Na; Zhang, Jun; Zhang, Yanshen; Yang, Xiaoli; Luo, Yifan; Zhang, Bobo; Xu, Zhixue; Zhu, Zhenhua; Yang, Xiuyan; Yan, Yuan; Lin, Biao; Wang, Shen; Chen, Da; Ye, Caichao; Ding, Yan; Lou, Mingliang; Wu, Qingcui; Hou, Zhanfeng; Zhang, Keren; Liang, Ziming; Wei, Anqi; Wang, Bianbian; Wang, Changhe; Jiang, Nan; Zhang, Wenqing; Xiao, Guozhi; Ma, Cong; Ren, Yan; Qi, Xiangbing; Han, Weiping; Wang, Chao; Rao, Feng
Source
Nature Metabolism. 3(10):1400-1414
Subject
Language
English
ISSN
2522-5812
Abstract
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.
Syt7-dependent pancreatic insulin release is shown to be mediated by 5-IP7 in response to parasympathetic stimulation of the GPCR M3R.
Syt7-dependent pancreatic insulin release is shown to be mediated by 5-IP