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 G_αq–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 G_q-coupled GPCR stimulation to unclamp Syt7-dependent, and perhaps other, exocytotic events.

5-二磷酸肌醇五磷酸 (5-IP ₇ ) 是一种与各种细胞过程相关的信号代谢物。细胞外刺激如何引发 5-IP ₇信号仍不清楚。在这里，我们显示 β 细胞中的 5-IP ₇介导突触结合蛋白 7 (Syt7) 依赖性胰岛素释放的副交感神经刺激。从机制上讲，迷走神经刺激和毒蕈碱性乙酰胆碱受体的激活会触发 G _αq –PLC–PKC–PKD 依赖性信号并激活 IP6K1（5-IP ₇合酶）。尽管 5-IP ₇及其前体 IP ₆都与 PIP ₂竞争结合 Syt7，但 Ca ²⁺选择性结合 5-IP ₇具有高亲和力，释放 Syt7，使含胰岛素的囊泡与细胞膜融合。β 细胞特异性 IP6K1 缺失减少了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 IP6K1 突变体的小鼠表现出胰岛素释放增加、先天性高胰岛素血症和肥胖。缺乏 Syt7 的小鼠不存在这些表型。我们的研究提出了肌醇焦磷酸生理学的新概念框架，其中 5-IP ₇在周围神经系统和代谢器官之间的界面充当 GPCR 第二信使，传递 G _q偶联的 GPCR 刺激以松开 Syt7 依赖性，也许还有其他, 胞吐事件。