Syntaxin 2 Acts as Inhibitory SNARE for Insulin Granule Exocytosis

Of the four syntaxins (Syns) specialized for exocytosis, syntaxin-2 is the least understood. Here, we employed syntaxin-2/epimorphin knockout (KO) mice to examine the role of syntaxin-2 in insulin secretory granule (SG) exocytosis. Unexpectedly, syntaxin-2 KO mice exhibited paradoxical superior glucose homeostasis resulting from an enhanced insulin secretion. This was confirmed in vitro by pancreatic islet perifusion showing an amplified biphasic glucose‐stimulated insulin secretion (GSIS) arising from an increase in size of the readily-releasable pool of insulin SGs and enhanced SG pool refilling. The increase in insulin exocytosis was attributed mainly from an enhanced recruitment of the larger pool of newcomer SGs that undergoes no residence time on plasma membrane before fusion, and to lesser extent also the predocked SGs. Consistently, syntaxin-2 depletion resulted in stimulation-induced increase in abundance of exocytotic complexes we previous demonstrated to mediate the fusion of newcomer SGs (Syn‐3/VAMP8/SNAP25/Munc18b) and predocked SGs (Syn-1A/VAMP2/SNAP25/Muncn18a). This work is first to show in mammals that syntaxin-2 could function as inhibitory SNARE protein, which when relieved, could promote exocytosis in pancreatic islet β-cells. Thus, syntaxin-2 may serve as a potential target to treat diabetes.