,Endophilin A2 regulates calcium-activated chloride channel activity via selective autophagy-mediate

• 作 者: Can-zhao Liu Fei-ya Li Xiao-fei Lv Ming-ming Ma Xiang-yu Li Cai-xia Lin Guan-lei Wang Yong-yuan Guan
• 机 构: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080,
• 出 处: 中国药理学报（英文版）
• 发表日期: 2020年2期
• 关键词: TMEM16A Ca2+-activated chloride channel basilar smooth muscle cells angiotensin

TMEM16A Ca2+-activated chloride channel (CaCC) plays an essential role in vascular homeostasis.In this study we investigated the molecular mechanisms underlying downregulation of TMEM16A CaCC activity during hypertension.In cultured basilar artery smooth muscle cells (BASMCs) isolated from 2k2c renohypertesive rats,treatment with angiotensin Ⅱ (0.125-1 μM) dosedependently increased endophilin A2 levels and decreased TMEM16A expression.Similar phenomenon was observed in basilar artery isolated from 2k2c rats.We then used whole-cell recording to examine whether endophilin A2 could regulate TMEM16A CaCC activity in BASMCs and found that knockdown of endophilin A2 significantly enhanced CaCC activity,whereas overexpression of endophilin A2 produced the opposite effect.Overexpression of endophilin A2 did not affect the TMEM16A mRNA level,but markedly decreased TMEM 16A protein level in BASMCs by inducing ubiquitination and autophagy of TMEM16A.Ubiquitin-binding receptor p62 (SQSTM1) could bind to ubiquitinated TMEM16A and resulted in a process of TMEM16A proteolysis in autophagosome/lysosome.These data provide new insights into the regulation of TMEM16A CaCC activity by endophilin A2 in BASMCs,which partly explains the mechanism of angiotensin-Ⅱ-induced TMEM16A inhibition during hypertension-induced vascular remodeling.