Niclosamide potentiates TMEM16A and induces vasoconstriction

• Type of Material: Article
• Authors: Pengfei Liang, Duke University; Yui Chun S. Wan, Duke University; Kuai Yu, Emory University; H. Criss Hartzell, Emory University; Huanghe Yang, Duke University
• Language: English
• Date: 2023-08-02
• Publisher: NIH
• Publication Version: Preprint (Prior to Peer Review)
• Copyright Statement: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): https://doi.org/10.1101%2F2023.07.31.551400
• Title of Journal or Parent Work: bioRxiv
• Grant/Funding Information: This work was supported by the NIH-DP2GM126898 grant (awarded to H.Y.), NIH R01-132598 to HCH) and AHA postdoctoral fellowship to P.L. (#903807).
• Keywords: ANO1; CaCC; Niclosamide; TMEM16A; Blood vessel
• Research Categories: Biology, Cell; Biology, Molecular

Abstract

The TMEM16A calcium-activated chloride channel is a promising therapeutic target for various diseases. Niclosamide, an anthelmintic medication, has been considered as a TMEM16A inhibitor for treating asthma and chronic obstructive pulmonary disease, but was recently found to possess broad-spectrum off-target effects. Here we show that, under physiological conditions, niclosamide acutely potentiates TMEM16A without having any inhibitory effect. Our computational and functional characterizations pinpoint a putative niclosamide binding site on the extracellular side of TMEM16A. Mutations in this site attenuate the potentiation. Moreover, niclosamide potentiates endogenous TMEM16A in vascular smooth muscle cells, triggers intracellular calcium increase, and constricts the murine mesenteric artery. Our findings advise caution when considering niclosamide as a TMEM16A inhibitor to treat diseases such as asthma, COPD, and hypertension. The identification of the putative niclosamide binding site provides insights into the mechanism of TMEM16A pharmacological modulation, shining light on developing specific TMEM16A modulators to treat human diseases.