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  • SNAP23 depletion enables more SNAP25/calcium channel excitosome formation to increase insulin exocytosis in type 2 diabetes.

SNAP23 depletion enables more SNAP25/calcium channel excitosome formation to increase insulin exocytosis in type 2 diabetes.

JCI insight (2020-02-14)
Tao Liang, Tairan Qin, Fei Kang, Youhou Kang, Li Xie, Dan Zhu, Subhankar Dolai, Dafna Greitzer-Antes, Robert K Baker, Daorong Feng, Eva Tuduri, Claes-Goran Ostenson, Timothy J Kieffer, Kate Banks, Jeffrey E Pessin, Herbert Y Gaisano
ABSTRACT

SNAP23 is the ubiquitous SNAP25 isoform that mediates secretion in non-neuronal cells, similar to SNAP25 in neurons. However, some secretory cells like pancreatic islet β cells contain an abundance of both SNAP25 and SNAP23, where SNAP23 is believed to play a redundant role to SNAP25. We show that SNAP23, when depleted in mouse β cells in vivo and human β cells (normal and type 2 diabetes [T2D] patients) in vitro, paradoxically increased biphasic glucose-stimulated insulin secretion corresponding to increased exocytosis of predocked and newcomer insulin granules. Such effects on T2D Goto-Kakizaki rats improved glucose homeostasis that was superior to conventional treatment with sulfonylurea glybenclamide. SNAP23, although fusion competent in slower secretory cells, in the context of β cells acts as a weak partial fusion agonist or inhibitory SNARE. Here, SNAP23 depletion promotes SNAP25 to bind calcium channels more quickly and longer where granule fusion occurs to increase exocytosis efficiency. β Cell SNAP23 antagonism is a strategy to treat diabetes.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-Syntaxin-1A antibody, Rabbit monoclonal, recombinant, expressed in HEK 293 cells, clone RM367, purified immunoglobulin
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Anti-Glucagon antibody, Mouse monoclonal, clone K79bB10, purified from hybridoma cell culture
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Anti-Insulin antibody, Mouse monoclonal, clone K36AC10, purified from hybridoma cell culture