CLCA2 is a positive regulator of store-operated calcium entry and TMEM16A

The Chloride Channel Accessory (CLCA) protein family was first characterized as regulators of calcium-activated chloride channel (CaCC) currents (I-cacc), but the mechanism has not been fully established. We hypothesized that CLCAs might regulate I-cacc by modulating intracellular calcium levels. In cells stably expressing human CLCA2 or vector, we found by calcium imaging that CLCA2 moderately enhanced intracellular-store release but dramatically increased store-operated entry of calcium upon cytosolic depletion. Moreover, another family member, CLCA1, produced similar effects on intracellular calcium mobilization. Co-immunoprecipitation revealed that CLCA2 interacted with the plasma membrane store-operated calcium channel ORAI-1 and the ER calcium sensor STIM-1. The effect of CLCA2 on I-cacc was tested in HEK293 stably expressing calcium-activated chloride channel TMEM16A. Co-expression of CLCA2 nearly doubled I-cacc in response to a calcium ionophore. These results unveil a new mechanism by which CLCA family members activate I-cacc and suggest a broader role in calcium-dependent processes.