PDF(Pubmed)
Abstract：
Glucose-stimulated insulin secretion (GSIS) in pancreatic islet β-cells primarily relies on electrophysiological processes. Previous research highlighted the regulatory role of KCNH6, a member of the Kv channel family, in governing GSIS through its influence on β-cell electrophysiology. In this study, we unveil a novel facet of KCNH6\'s function concerning insulin granule exocytosis, independent of its conventional electrical role. Young mice with β-cell-specific KCNH6 knockout (βKO) exhibited impaired glucose tolerance and reduced insulin secretion, a phenomenon not explained by electrophysiological processes alone. Consistently, islets from KCNH6-βKO mice exhibited reduced insulin secretion, conversely, the overexpression of KCNH6 in murine pancreatic islets significantly enhanced insulin release. Moreover, insulin granules lacking KCNH6 demonstrated compromised docking capabilities and a reduced fusion response upon glucose stimulation. Crucially, our investigation unveiled a significant interaction between KCNH6 and the SNARE protein regulator, Munc18-1, a key mediator of insulin granule exocytosis. These findings underscore the critical role of KCNH6 in the regulation of insulin secretion through its interaction with Munc18-1, providing a promising and novel avenue for enhancing our understanding of the Kv channel in diabetes mechanisms.
摘要：
胰岛β细胞中葡萄糖刺激的胰岛素分泌（GSIS）主要依赖于电生理过程。先前的研究强调了KCNH6的调节作用，KCNH6是Kv通道家族的成员，通过其对β细胞电生理的影响来控制GSIS。在这项研究中,我们揭示了KCNH6关于胰岛素颗粒胞吐作用的一个新方面，独立于其传统的电气作用。β细胞特异性KCNH6基因敲除（βKO）的年轻小鼠表现出糖耐量受损和胰岛素分泌减少，一种不能单独用电生理过程解释的现象。始终如一，来自KCNH6-βKO小鼠的胰岛表现出胰岛素分泌减少，相反,小鼠胰岛中KCNH6的过度表达显著增强了胰岛素的释放。此外，缺乏KCNH6的胰岛素颗粒在葡萄糖刺激后显示出对接能力受损和融合反应降低.至关重要的是，我们的研究揭示了KCNH6和SNARE蛋白调节因子之间的显著相互作用，Munc18-1，胰岛素颗粒胞吐的关键介质。这些发现强调了KCNH6通过其与Munc18-1的相互作用在调节胰岛素分泌中的关键作用，为增强我们对糖尿病机制中Kv通道的理解提供了有希望的新颖途径。
