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 β 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 β‐cells remains unclear. In this study, we found that KCNH6 exhibited mainly ER localization and Kcnh6 β‐cell‐specific knockout (βKO) mice suffered from abnormal glucose tolerance and impaired insulin secretion in adulthood. ER Ca2+ store was overloaded in islets of βKO mice, which contributed to ER stress and ER stress‐induced apoptosis in β cells. Next, we verified that ethanol treatment induced increases in ER Ca2+ store and apoptosis in pancreatic β 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 βKO mice, restored ER Ca2+ overload and attenuated ER stress in β 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 β cells from ER stress and apoptosis. In conclusion, our study reveals the protective potential of KCNH6‐targeting drugs in ER stress‐induced diabetes. KCNH6 promotes the development of a K+ countercurrent on the ER membrane to balance the negative charge produced by ER Ca2+ efflux. KCNH6 knockout prevents Ca2+ efflux and results in β‐cell ER Ca2+ overload and ER stress.