KCNH6 is essential for insulin secretion by regulating intracellular ER Ca²⁺ store

Appropriate Ca2+ concentration in the endoplasmic reticulum (ER), modulating cytosolic Ca2+ signal, serves significant roles in physiological function of pancreatic beta cells. To maintaining ER homeostasis, Ca2+ movement across the ER membrane is always accompanied by a simultaneous K+ flux in the opposite direction. KCNH6 was proven to modulate insulin secretion by controlling plasma membrane action potential duration and intracellular Ca2+ influx. Meanwhile, the specific function of KCNH6 in pancreatic beta-cells remains unclear. In this study, we found that KCNH6 exhibited mainly ER localization and Kcnh6 beta-cell-specific knockout (beta KO) mice suffered from abnormal glucose tolerance and impaired insulin secretion in adulthood. ER Ca2+ store was overloaded in islets of beta KO mice, which contributed to ER stress and ER stress-induced apoptosis in beta cells. Next, we verified that ethanol treatment induced increases in ER Ca2+ store and apoptosis in pancreatic beta cells, whereas adenovirus-mediated KCNH6 overexpression in islets attenuated ethanol-induced ER stress and apoptosis. In addition, tail-vein injections of KCNH6 lentivirus rescued KCNH6 expression in beta KO mice, restored ER Ca2+ overload and attenuated ER stress in beta cells, which further confirms that KCNH6 protects islets from ER stress and apoptosis. These data suggest that KCNH6 on the ER membrane may help to stabilize intracellular ER Ca2+ stores and protect beta cells from ER stress and apoptosis. In conclusion, our study reveals the protective potential of KCNH6-targeting drugs in ER stress-induced diabetes.