Niclosamide potentiates TMEM16A and induces vasoconstriction

Area of Science:

• Molecular pharmacology
• Ion channel function
• Drug discovery

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 exhibits off-target effects.

Purpose of the Study:

• To investigate the actual effect of niclosamide on TMEM16A channel activity under physiological conditions.
• To identify the binding site and mechanism of niclosamide interaction with TMEM16A.
• To evaluate the physiological consequences of niclosamide-induced TMEM16A potentiation.

Main Methods:

• Computational modeling and functional electrophysiology to characterize niclosamide-TMEM16A interactions.
• Site-directed mutagenesis to probe the identified binding site.
• Experiments on vascular smooth muscle cells and murine mesenteric arteries to assess physiological effects.

Main Results:

• Niclosamide acutely potentiates TMEM16A channel activity at physiological calcium concentrations and voltages.
• A putative extracellular binding site for niclosamide on TMEM16A was identified, and mutations here reduced potentiation.
• Niclosamide potentiated endogenous TMEM16A in vascular smooth muscle cells, leading to calcium increase and arterial constriction.

Conclusions:

• Niclosamide acts as a potentiator, not an inhibitor, of TMEM16A channels under physiological conditions.
• Clinical use of niclosamide as a TMEM16A inhibitor warrants caution due to its unexpected potentiation effect.
• The identified binding site offers a basis for developing novel, specific TMEM16A modulators.