Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Department of Cellular and Physiological Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
JCI Insight. 2020 Feb 13;5(3):129694. doi: 10.1172/jci.insight.129694.
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.
突触融合蛋白 23（SNAP23）是普遍存在的突触融合蛋白 25（SNAP25）同工型，在非神经元细胞中介导分泌，类似于神经元中的 SNAP25。然而，一些分泌细胞，如胰岛β细胞，同时含有丰富的 SNAP25 和 SNAP23，SNAP23 被认为在 SNAP25 中发挥冗余作用。我们发现，体内敲除小鼠β细胞和体外敲除人β细胞（正常和 2 型糖尿病[T2D]患者）中的 SNAP23，会反直觉地增加双相葡萄糖刺激的胰岛素分泌，对应于预停泊和新出现的胰岛素颗粒的胞吐作用增加。这种对 Goto-Kakizaki 大鼠 2 型糖尿病的影响改善了葡萄糖稳态，优于常规使用磺酰脲类格列本脲的治疗效果。尽管 SNAP23 在较慢的分泌细胞中具有融合能力，但在β细胞的情况下，它充当弱的部分融合激动剂或抑制性 SNARE。在这里，SNAP23 的耗竭促使 SNAP25 更快地与钙通道结合，并持续更长时间，从而促进颗粒融合，增加胞吐效率。β细胞 SNAP23 拮抗是治疗糖尿病的一种策略。
