Calcium-Activated Cl– Channels

Ca²⁺-activated Cl^– channels (CaCCs) are ubiquitously expressed and perform functions as diverse as fast block to polyspermy, regulation of blood pressure and gut peristalsis, sensation of noxious stimuli, and fluid secretion. CaCCs are encoded by genes from two different families, TMEM16/anoctamins and bestrophins. While both TMEM16s and bestrophins are gated open to conduct anions by the direct binding of cytosolic Ca²⁺, they have very different structures and mechanisms of gating. TMEM16s are double-barreled dimers with each protomer gated by Ca²⁺ binding to a site in the voltage field near the permeation pathway. In contrast, bestrophins are pentamers that form a single pore gated by Ca²⁺ binding sites located on the surface of the protein at the interface between the membrane and cytosol. The features of the Ca²⁺ binding sites and permeation pathways of these proteins are unique and intriguing. Mutations in BEST1 are linked to a type of inherited retinal degeneration, while TMEM16A overexpression is linked to poor prognosis of certain cancers. While astounding progress has been made in understanding these channels in the past decade, there remains much to be learned.