Functional Interaction Between Caveolin 1 and LRRC8-Mediated Volume-Regulated Anion Channel
Volume-regulated anion channel (VRAC), constituted by leucine-rich repeat-containing 8 (LRRC8) heteromers, is crucial for volume homeostasis in vertebrate cells. This widely expressed channel has been associated with membrane potential modulation, proliferation, migration, apoptosis, and glutamate r...
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doaj-18adb44fc0644d9bb3d7d8bd2aa5d2c72021-10-01T04:53:25ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2021-10-011210.3389/fphys.2021.691045691045Functional Interaction Between Caveolin 1 and LRRC8-Mediated Volume-Regulated Anion ChannelMikel Rezola0Aida Castellanos1Xavier Gasull2Xavier Gasull3Núria Comes4Núria Comes5Neurophysiology Laboratory, Physiology Unit, Department of Biomedicine, Medical School, Institute of Neurosciences, University of Barcelona, Barcelona, SpainNeurophysiology Laboratory, Physiology Unit, Department of Biomedicine, Medical School, Institute of Neurosciences, University of Barcelona, Barcelona, SpainNeurophysiology Laboratory, Physiology Unit, Department of Biomedicine, Medical School, Institute of Neurosciences, University of Barcelona, Barcelona, SpainInstitut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, SpainNeurophysiology Laboratory, Physiology Unit, Department of Biomedicine, Medical School, Institute of Neurosciences, University of Barcelona, Barcelona, SpainInstitut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, SpainVolume-regulated anion channel (VRAC), constituted by leucine-rich repeat-containing 8 (LRRC8) heteromers, is crucial for volume homeostasis in vertebrate cells. This widely expressed channel has been associated with membrane potential modulation, proliferation, migration, apoptosis, and glutamate release. VRAC is activated by cell swelling and by low cytoplasmic ionic strength or intracellular guanosine 5′-O-(3-thiotriphosphate) (GTP-γS) in isotonic conditions. Despite the substantial number of studies that characterized the biophysical properties of VRAC, its mechanism of activation remains a mystery. Different evidence suggests a possible effect of caveolins in modulating VRAC activity: (1) Caveolin 1 (Cav1)-deficient cells display insignificant swelling-induced Cl– currents mediated by VRAC, which can be restored by Cav1 expression; (2) Caveolin 3 (Cav3) knockout mice display reduced VRAC currents; and (3) Interaction between LRRC8A, the essential subunit for VRAC, and Cav3 has been found in transfected human embryonic kidney 293 (HEK 293) cells. In this study, we demonstrate a physical interaction between endogenous LRRC8A and Cav1 proteins, that is enhanced by hypotonic stimulation, suggesting that this will increase the availability of the channel to Cav1. In addition, LRRC8A targets plasma membrane regions outside caveolae of HEK 293 cells where it associates with non-caveolar Cav1. We propose that a rise in cell membrane tension by hypotonicity would flatten caveolae, as described previously, increasing the amount of Cav1 outside of caveolar structures interacting with VRAC. Besides, the expression of Cav1 in HEK Cav1- cells increases VRAC current density without changing the main biophysical properties of the channel. The present study provides further evidence on the relevance of Cav1 on the activation of endothelial VRAC through a functional molecular interaction.https://www.frontiersin.org/articles/10.3389/fphys.2021.691045/fullvolume-regulated anion channelLRRC8Acaveolinsswelling-activated chloride currentprotein interactionchannel surface localization |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Mikel Rezola Aida Castellanos Xavier Gasull Xavier Gasull Núria Comes Núria Comes |
spellingShingle |
Mikel Rezola Aida Castellanos Xavier Gasull Xavier Gasull Núria Comes Núria Comes Functional Interaction Between Caveolin 1 and LRRC8-Mediated Volume-Regulated Anion Channel Frontiers in Physiology volume-regulated anion channel LRRC8A caveolins swelling-activated chloride current protein interaction channel surface localization |
author_facet |
Mikel Rezola Aida Castellanos Xavier Gasull Xavier Gasull Núria Comes Núria Comes |
author_sort |
Mikel Rezola |
title |
Functional Interaction Between Caveolin 1 and LRRC8-Mediated Volume-Regulated Anion Channel |
title_short |
Functional Interaction Between Caveolin 1 and LRRC8-Mediated Volume-Regulated Anion Channel |
title_full |
Functional Interaction Between Caveolin 1 and LRRC8-Mediated Volume-Regulated Anion Channel |
title_fullStr |
Functional Interaction Between Caveolin 1 and LRRC8-Mediated Volume-Regulated Anion Channel |
title_full_unstemmed |
Functional Interaction Between Caveolin 1 and LRRC8-Mediated Volume-Regulated Anion Channel |
title_sort |
functional interaction between caveolin 1 and lrrc8-mediated volume-regulated anion channel |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Physiology |
issn |
1664-042X |
publishDate |
2021-10-01 |
description |
Volume-regulated anion channel (VRAC), constituted by leucine-rich repeat-containing 8 (LRRC8) heteromers, is crucial for volume homeostasis in vertebrate cells. This widely expressed channel has been associated with membrane potential modulation, proliferation, migration, apoptosis, and glutamate release. VRAC is activated by cell swelling and by low cytoplasmic ionic strength or intracellular guanosine 5′-O-(3-thiotriphosphate) (GTP-γS) in isotonic conditions. Despite the substantial number of studies that characterized the biophysical properties of VRAC, its mechanism of activation remains a mystery. Different evidence suggests a possible effect of caveolins in modulating VRAC activity: (1) Caveolin 1 (Cav1)-deficient cells display insignificant swelling-induced Cl– currents mediated by VRAC, which can be restored by Cav1 expression; (2) Caveolin 3 (Cav3) knockout mice display reduced VRAC currents; and (3) Interaction between LRRC8A, the essential subunit for VRAC, and Cav3 has been found in transfected human embryonic kidney 293 (HEK 293) cells. In this study, we demonstrate a physical interaction between endogenous LRRC8A and Cav1 proteins, that is enhanced by hypotonic stimulation, suggesting that this will increase the availability of the channel to Cav1. In addition, LRRC8A targets plasma membrane regions outside caveolae of HEK 293 cells where it associates with non-caveolar Cav1. We propose that a rise in cell membrane tension by hypotonicity would flatten caveolae, as described previously, increasing the amount of Cav1 outside of caveolar structures interacting with VRAC. Besides, the expression of Cav1 in HEK Cav1- cells increases VRAC current density without changing the main biophysical properties of the channel. The present study provides further evidence on the relevance of Cav1 on the activation of endothelial VRAC through a functional molecular interaction. |
topic |
volume-regulated anion channel LRRC8A caveolins swelling-activated chloride current protein interaction channel surface localization |
url |
https://www.frontiersin.org/articles/10.3389/fphys.2021.691045/full |
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