Open AccessCLCA2 is a positive regulator of store-operated calcium entry and TMEM16A
Author(s) -
Aarushi Sharma,
Grace Ramena,
Yufang Yin,
Louis S. Premkumar,
Randolph C. Elble
Publication year - 2018
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0196512
Subject(s) - chloride channel , calcium , calcium in biology , microbiology and biotechnology , hek 293 cells , intracellular , chemistry , cytosol , voltage dependent calcium channel , regulator , calcium channel , immunoprecipitation , t type calcium channel , biophysics , biochemistry , biology , receptor , gene , organic chemistry , enzyme
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.