Endophilin A2 regulates calcium-activated chloride channel activity via selective autophagy-mediated TMEM16A degradation

Authors: Can-zhao Liu1, Fei-ya Li1,2,3, Xiao-fei Lv1, Ming-ming Ma1, Xiang-yu Li1, Cai-xia Lin1, Guan-lei Wang1, Yong-yuan Guan1
1 Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
2 Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
3 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
Correspondence to: Can-zhao Liu:, Yong-yuan Guan:,
DOI: 10.1038/s41401-019-0298-5
Received: 21 April 2019
Accepted: 6 August 2019
Advance online: 4 September 2019


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) dose-dependently 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 TMEM16A 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.
Keywords: TMEM16A; Ca2+-activated chloride channel; basilar smooth muscle cells; angiotensin II; endophilin A2; ubiquitination; autophagy; hypertension; vascular remodeling

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