Niclosamide potentiates TMEM16A and induces vasoconstriction.
Pengfei Liang1, Yui Chun S Wan1, Kuai Yu2
1Department of Biochemistry, Duke University School of Medicine, NC 27710, USA.
Biorxiv : the Preprint Server for Biology
|August 14, 2023
Summary
Niclosamide unexpectedly potentiates, rather than inhibits, the TMEM16A channel, contrary to previous assumptions. This finding cautions against using niclosamide for conditions like asthma or hypertension.
Area of Science:
- Ion channel pharmacology
- Molecular mechanisms of disease
Background:
- The TMEM16A calcium-activated chloride channel is a key target for treating diseases like asthma and COPD.
- Niclosamide, an anthelmintic, was investigated as a TMEM16A inhibitor but has known off-target effects.
Approach:
- Investigated niclosamide's effect on TMEM16A under physiological conditions.
- Utilized computational and functional characterizations to identify a binding site.
- Examined niclosamide's impact on endogenous TMEM16A in vascular smooth muscle cells.
Key Points:
- Niclosamide acutely potentiates TMEM16A, showing no inhibitory effect.
- A putative extracellular binding site for niclosamide on TMEM16A was identified.
- Niclosamide potentiates endogenous TMEM16A, increasing intracellular calcium and constricting arteries.
Conclusions:
- Niclosamide's potentiation of TMEM16A necessitates caution for therapeutic use in asthma, COPD, and hypertension.
- The identified binding site offers insights for developing specific TMEM16A modulators.
- Further research is needed to understand the precise mechanisms and therapeutic implications.
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