5-IP is a GPCR messenger mediating neural control of synaptotagmin-dependent insulin exocytosis and glucose homeostasis.

5-diphosphoinositol pentakisphosphate (5-IP) is a signalling metabolite linked to various cellular processes. How extracellular stimuli elicit 5-IP signalling remains unclear. Here we show that 5-IP in β cells mediates parasympathetic stimulation of synaptotagmin-7 (Syt7)-dependent insulin release. Mechanistically, vagal stimulation and activation of muscarinic acetylcholine receptors triggers G-PLC-PKC-PKD-dependent signalling and activates IP6K1, the 5-IP synthase. Whereas both 5-IP and its precursor IP compete with PIP for binding to Syt7, Ca selectively binds 5-IP 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-IP acts as a GPCR second messenger at the interface between peripheral nervous system and metabolic organs, transmitting G-coupled GPCR stimulation to unclamp Syt7-dependent, and perhaps other, exocytotic events.