Modulating Ca²⁺ signals: a common theme for TMEM16, Ist2, and TMC.

Since the discovery of TMEM16A (anoctamin 1, ANO1) as Ca(2+)-activated Cl(-) channel, the protein was found to serve different physiological functions, depending on the type of tissue. Subsequent reports on other members of the anoctamin family demonstrated a broad range of yet poorly understood properties. Compromised anoctamin function is causing a wide range of diseases, such as hearing loss (ANO2), bleeding disorder (ANO6), ataxia and dystonia (ANO3, 10), persistent borrelia and mycobacteria infection (ANO10), skeletal syndromes like gnathodiaphyseal dysplasia and limb girdle muscle dystrophy (ANO5), and cancer (ANO1, 6, 7). Animal models demonstrate CF-like airway disease, asthma, and intestinal hyposecretion (ANO1). Although present data indicate that ANO1 is a Ca(2+)-activated Cl(-) channel, it remains unclear whether all anoctamins form plasma membrane-localized or intracellular chloride channels. We find Ca(2+)-activated Cl(-) currents appearing by expression of most anoctamin paralogs, including the Nectria haematococca homologue nhTMEM16 and the yeast homologue Ist2. As recent studies show a role of anoctamins, Ist2, and the related transmembrane channel-like (TMC) proteins for intracellular Ca(2+) signaling, we will discuss the role of these proteins in generating compartmentalized Ca(2+) signals, which may give a hint as to the broad range of cellular functions of anoctamins.