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SNAP23 depletion enables more SNAP25/calcium channel excitosome formation to increase insulin exocytosis in type 2 diabetes
Tao Liang, … , Jeffrey E. Pessin, Herbert Y. Gaisano
Tao Liang, … , Jeffrey E. Pessin, Herbert Y. Gaisano
Published February 13, 2020
Citation Information: JCI Insight. 2020;5(3):e129694. https://doi.org/10.1172/jci.insight.129694.
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Research Article Endocrinology Metabolism

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

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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.

Authors

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

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Figure 4

SNAP23 depletion increases GSIS in normal human islets.

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SNAP23 depletion increases GSIS in normal human islets.
(A) Ad-SNAP23 sh...
(A) Ad-SNAP23 shRNA/mCherry treatment (48 hours) of human islets (see Supplemental Table 1 for details on human donors) effectively depleted SNAP23 (SNAP23-KD) as shown on confocal imaging (left) and islet protein levels (right). Scale bars: 100 μm. Left: SNAP23 is abundant in human islet β cells (top) and not affected by Ad-scrambled shRNA/mCherry (middle). SNAP23 was severely depleted by Ad-SNAP23 shRNA/mCherry treatment (bottom), wherein the few SNAP23-positive cells are mCherry-negative, allowing calculation of the ratio of SNAP23-positive area per islet area (right graph, n = 19 islets from each group). Right: Western blots of islets show reduction in SNAP23 protein levels by Ad-SNAP23 shRNA/mCherry but no effects on the other exocytotic proteins. Shown are representative of 3 experiments, with analysis of n = 3 in Supplemental Figure 4A. (B) SNAP23-KD of human islets increased first- and second-phase GSIS compared with Ad-scrambled shRNA/mCherry–treated (Control) islets. AUC analysis in bottom from n = 4 for each group, from 4 independent experiments. (C) These human islets were then dispersed into single cells for patch-clamp Cm measurements performed on mCherry-positive β cells, which showed that SNAP23-KD β cells exhibited increased exocytosis. Top: Representative recordings. Bottom left: Cumulative changes in cell capacitance normalized to basal cell membrane capacitance (fF/pF) in Control versus SNAP23-KD (n = 15 cells) β cells, and shown as (bottom right) summary graph (Control: n = 14 cells, SNAP23-KD: n = 15 cells). *P < 0.05; **P < 0.01; ***P < 0.001. Statistical significance was assessed by 2-tailed Student’s t test.

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