5-IP7 is a GPCR Messenger Mediating Neural Control of Insulin Exocytosis and Glucose Homeostasis
LI Na, RAO Feng*
5-IP7 (5-diphosphoinositol pentakisphosphate) is an enigmatic signaling metabolite. This study elucidated a GPCR pathway that utilized 5-IP7 as a 2nd messenger to mediate neural control of endocrine secretion and metabolic homeostasis. Specifically, vagal stimulation activates IP6K1, the 5-IP7 synthase, is activated via a muscarinic acetylcholine receptor-Gαq-PLC-PKC/PKD phosphorylation axis in pancreas. Upon parasympathetic nerve input, this pathway activates by mediating parasympathetic stimulation of Syt7 (synaptotagmin-7)-dependent insulin release. Both 5-IP7 and its precursor IP6 compete with PIP2 for Syt7. However, Ca2+ selectively binds 5-IP7 with high affinity, freeing Syt7 to promote vesicle membrane interaction. β-cell specific IP6K1 deletion diminishes insulin secretion and glucose clearance elicited by muscarinic stimulation; whereas mice carrying a phosphorylation-mimic, hyperactive IP6K1 mutant display augmented insulin release, congenital hyperinsulinism, and obesity. These phenotypes are absent in a Syt7 null background. This study suggests a new conceptual framework to understand inositol pyrophosphate physiology: 5-IP7 is a metabolic messenger for GPCR signaling at the interface between peripheral nervous system and metabolic organs, where it transmits Gq-coupled GPCR stimulation to unclamp Syt7-dependent and perhaps other exocytotic events.
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