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

PloS One
Aarushi SharmaRandolph C Elble

Abstract

The Chloride Channel Accessory (CLCA) protein family was first characterized as regulators of calcium-activated chloride channel (CaCC) currents (ICaCC), but the mechanism has not been fully established. We hypothesized that CLCAs might regulate ICaCC 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 ICaCC was tested in HEK293 stably expressing calcium-activated chloride channel TMEM16A. Co-expression of CLCA2 nearly doubled ICaCC in response to a calcium ionophore. These results unveil a new mechanism by which CLCA family members activate ICaCC and suggest a broader role in calcium-dependent processes.

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Citations

Jun 12, 2019·Proceedings of the National Academy of Sciences of the United States of America·David CrottèsLily Yeh Jan
Oct 17, 2018·International Journal of Molecular Sciences·Mélanie LambertFabrice Antigny
Aug 14, 2019·Oncology Letters·Xiaohang PanJialiang Gan
Aug 30, 2020·Nature Communications·Ines CabritaBjörn Buchholz
Jun 14, 2019·Omics : a Journal of Integrative Biology·Jie LiuBiaoyang Lin
Jan 25, 2021·Computers in Biology and Medicine·Manoj Kumar SinghSrinivasan Ramachandran
Mar 4, 2021·American Journal of Physiology. Lung Cellular and Molecular Physiology·Derek B McMahonRobert J Lee
May 6, 2021·International Journal of Molecular Sciences·Dmitrii KolesnikovAlexey Shalygin
Nov 18, 2021·American Journal of Physiology. Cell Physiology·Adriana M Fresquez, Carl White

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Methods Mentioned

BETA
PCR
confocal microscopy
immunoprecipitation
Immunoprecipitations
Co-immunoprecipitation
transfect
pulled down
co-IP

Software Mentioned

IP Lab3
Licor
LabView

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