An outer-pore gate modulates the pharmacology of the TMEM16A channel
Ria L. Dinsdale, Tanadet Pipatpolkai, Emilio Agostinelli, Angela J. Russell, Phillip J. Stansfeld, Paolo Tammaro
Abstract
Significance The TMEM16A calcium-gated chloride channels participate in a range of vital physiological functions. TMEM16A channels are desirable new drug targets as their dysfunction can lead to pathology. In spite of this, their pharmacology is still in its infancy. Gaining insight into the mode of action and binding sites for test compounds forms the basis for the development of new TMEM16A-interacting drugs. Here, we demonstrate that intracellular calcium triggers a conformational change in the outer mouth of the channel, which enables entry of a small molecule into the pore. Characterization of this structural rearrangement defines a critical site for pharmacological intervention and reveals an aspect of calcium gating in the TMEM16A channel.