KCNH6 is essential for insulin secretion by regulating intracellular ER Ca 2+ store.

Autor: Xiong FR; Department of Endocrinology, Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Beijing Tongren Hospital, Capital Medical University, Beijing, China.; Laboratory for Clinical Medicine, Capital Medical University, Beijing, China., Lu J; Department of Endocrinology, Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Beijing Tongren Hospital, Capital Medical University, Beijing, China.; Laboratory for Clinical Medicine, Capital Medical University, Beijing, China., Zhu JJ; Department of Endocrinology, Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Beijing Tongren Hospital, Capital Medical University, Beijing, China.; Laboratory for Clinical Medicine, Capital Medical University, Beijing, China., Zhao RX; Department of Endocrinology, Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Beijing Tongren Hospital, Capital Medical University, Beijing, China.; Laboratory for Clinical Medicine, Capital Medical University, Beijing, China., Zhang YC; Department of Endocrinology, Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Beijing Tongren Hospital, Capital Medical University, Beijing, China.; Laboratory for Clinical Medicine, Capital Medical University, Beijing, China., Yang JK; Department of Endocrinology, Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Beijing Tongren Hospital, Capital Medical University, Beijing, China.; Laboratory for Clinical Medicine, Capital Medical University, Beijing, China.
Jazyk: angličtina
Zdroj: FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2024 Feb 29; Vol. 38 (4), pp. e23490.
DOI: 10.1096/fj.202302194RR
Abstrakt: Appropriate Ca 2+ concentration in the endoplasmic reticulum (ER), modulating cytosolic Ca 2+ signal, serves significant roles in physiological function of pancreatic β cells. To maintaining ER homeostasis, Ca 2+ 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 Ca 2+ 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 Ca 2+ 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 Ca 2+ 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 Ca 2+ 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 Ca 2+ 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.
(© 2024 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)
Databáze: MEDLINE
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