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5-IP7 is a GPCR messenger mediating neural control of synaptotagmin-dependent insulin exocytosis and glucose homeostasis
Nature Metabolism  (IF13.511),  Pub Date : 2021-10-18, DOI: 10.1038/s42255-021-00468-7
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, Caichao Ye, Yan Ding, Mingliang Lou, Qingcui Wu, Zhanfeng Hou, Keren Zhang, Ziming Liang, Anqi Wei, Bianbian Wang, Changhe Wang, Nan Jiang, Wenqing Zhang, Guozhi Xiao, Cong Ma, Yan Ren, Xiangbing Qi, Weiping Han, Chao Wang, Feng Rao

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.