Secreted CLCA1 modulates TMEM16A to activate Ca(2+)-dependent chloride currents in human cells

ELife
Monica Sala-RabanalTom J Brett

Abstract

Calcium-activated chloride channel regulator 1 (CLCA1) activates calcium-dependent chloride currents; neither the target, nor mechanism, is known. We demonstrate that secreted CLCA1 activates calcium-dependent chloride currents in HEK293T cells in a paracrine fashion, and endogenous TMEM16A/Anoctamin1 conducts the currents. Exposure to exogenous CLCA1 increases cell surface levels of TMEM16A and cellular binding experiments indicate CLCA1 engages TMEM16A on the surface of these cells. Altogether, our data suggest that CLCA1 stabilizes TMEM16A on the cell surface, thus increasing surface expression, which results in increased calcium-dependent chloride currents. Our results identify the first Cl(-) channel target of the CLCA family of proteins and establish CLCA1 as the first secreted direct modifier of TMEM16A activity, delineating a unique mechanism to increase currents. These results suggest cooperative roles for CLCA and TMEM16 proteins in influencing the physiology of multiple tissues, and the pathology of multiple diseases, including asthma, COPD, cystic fibrosis, and certain cancers.

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Citations

Aug 22, 2015·Expert Review of Respiratory Medicine·Tom J Brett
Nov 28, 2015·Mediators of Inflammation·Monica Sala-RabanalTom J Brett
Oct 7, 2016·Cell Death & Disease·Katherine HughesChristine J Watson
Jan 22, 2017·Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology·M KondoJ Tamaoki
Aug 30, 2018·American Journal of Physiology. Renal Physiology·Laura K SchenkHermann Pavenstädt
Dec 27, 2018·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Roberta BenedettoKarl Kunzelmann
Jan 11, 2019·American Journal of Physiology. Gastrointestinal and Liver Physiology·Cole B EnnsMatthew E Loewen
Apr 27, 2019·The European Respiratory Journal·Rita PappAndrea Olschewski
May 15, 2018·PloS One·Aarushi SharmaRandolph C Elble
Feb 22, 2018·Journal of Experimental & Clinical Cancer Research : CR·Yuan-Yuan QiangChao-Nan Qian
Mar 14, 2019·The Journal of General Physiology·Scott D ZawiejaMichael J Davis
Jan 15, 2019·The Journal of Clinical Investigation·Alejandro A PezzuloJoseph Zabner
Mar 22, 2019·Cancers·Karl KunzelmannRainer Schreiber
Jul 4, 2019·The Journal of Biological Chemistry·Maiwase TemboAnne E Carlson
Apr 11, 2020·International Journal of Molecular Sciences·Raquel CenteioKarl Kunzelmann
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Nov 7, 2020·Frontiers in Immunology·Conor McClenaghanColin G Nichols
Jun 3, 2021·International Journal of Molecular Sciences·Raquel CenteioKarl Kunzelmann

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Methods Mentioned

BETA
confocal microscopy
flow cytometry
transfection

Software Mentioned

FlowJo
pClamp
MultiClamp 700B Commander
GraphPad
CaBuf
Clampex JPCalc
AxioVision
LSM
ImageJ
Prism

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