Membrane cholesterol regulates TRPV4 function, cytoskeletal expression, and the cellular response to tension

Despite the association of cholesterol with debilitating pressure-related diseases such as glaucoma, heart disease, and diabetes, its role in mechanotransduction is not well understood. We investigated the relationship between mechanical strain, free membrane cholesterol, actin cytoskeleton, and the...

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Autores principales:	Monika Lakk, Grace F. Hoffmann, Aruna Gorusupudi, Eric Enyong, Amy Lin, Paul S. Bernstein, Trine Toft-Bertelsen, Nanna MacAulay, Michael H. Elliott, David Križaj
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	cell signaling cyclodextrins dyslipidemias eye/retina glaucoma lipid rafts Biochemistry QD415-436
Acceso en línea:	https://doaj.org/article/ddf84964e0c34f4f9e32ca66ec7cc420
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spelling	oai:doaj.org-article:ddf84964e0c34f4f9e32ca66ec7cc4202021-11-26T04:23:00ZMembrane cholesterol regulates TRPV4 function, cytoskeletal expression, and the cellular response to tension0022-227510.1016/j.jlr.2021.100145https://doaj.org/article/ddf84964e0c34f4f9e32ca66ec7cc4202021-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0022227521001279https://doaj.org/toc/0022-2275Despite the association of cholesterol with debilitating pressure-related diseases such as glaucoma, heart disease, and diabetes, its role in mechanotransduction is not well understood. We investigated the relationship between mechanical strain, free membrane cholesterol, actin cytoskeleton, and the stretch-activated transient receptor potential vanilloid isoform 4 (TRPV4) channel in human trabecular meshwork (TM) cells. Physiological levels of cyclic stretch resulted in time-dependent decreases in membrane cholesterol/phosphatidylcholine ratio and upregulation of stress fibers. Depleting free membrane cholesterol with m-β-cyclodextrin (MβCD) augmented TRPV4 activation by the agonist GSK1016790A, swelling and strain, with the effects reversed by cholesterol supplementation. MβCD increased membrane expression of TRPV4, caveolin-1, and flotillin. TRPV4 did not colocalize or interact with caveolae or lipid rafts, apart from a truncated ∼75 kDa variant partially precipitated by a caveolin-1 antibody. MβCD induced currents in TRPV4-expressing Xenopus laevis oocytes. Thus, membrane cholesterol regulates trabecular transduction of mechanical information, with TRPV4 channels mainly located outside the cholesterol-enriched membrane domains. Moreover, the biomechanical milieu itself shapes the lipid content of TM membranes. Diet, cholesterol metabolism, and mechanical stress might modulate the conventional outflow pathway and intraocular pressure in glaucoma and diabetes in part by modulating TM mechanosensing.Monika LakkGrace F. HoffmannAruna GorusupudiEric EnyongAmy LinPaul S. BernsteinTrine Toft-BertelsenNanna MacAulayMichael H. ElliottDavid KrižajElsevierarticlecell signalingcyclodextrinsdyslipidemiaseye/retinaglaucomalipid raftsBiochemistryQD415-436ENJournal of Lipid Research, Vol 62, Iss , Pp 100145- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cell signaling cyclodextrins dyslipidemias eye/retina glaucoma lipid rafts Biochemistry QD415-436
spellingShingle	cell signaling cyclodextrins dyslipidemias eye/retina glaucoma lipid rafts Biochemistry QD415-436 Monika Lakk Grace F. Hoffmann Aruna Gorusupudi Eric Enyong Amy Lin Paul S. Bernstein Trine Toft-Bertelsen Nanna MacAulay Michael H. Elliott David Križaj Membrane cholesterol regulates TRPV4 function, cytoskeletal expression, and the cellular response to tension
description	Despite the association of cholesterol with debilitating pressure-related diseases such as glaucoma, heart disease, and diabetes, its role in mechanotransduction is not well understood. We investigated the relationship between mechanical strain, free membrane cholesterol, actin cytoskeleton, and the stretch-activated transient receptor potential vanilloid isoform 4 (TRPV4) channel in human trabecular meshwork (TM) cells. Physiological levels of cyclic stretch resulted in time-dependent decreases in membrane cholesterol/phosphatidylcholine ratio and upregulation of stress fibers. Depleting free membrane cholesterol with m-β-cyclodextrin (MβCD) augmented TRPV4 activation by the agonist GSK1016790A, swelling and strain, with the effects reversed by cholesterol supplementation. MβCD increased membrane expression of TRPV4, caveolin-1, and flotillin. TRPV4 did not colocalize or interact with caveolae or lipid rafts, apart from a truncated ∼75 kDa variant partially precipitated by a caveolin-1 antibody. MβCD induced currents in TRPV4-expressing Xenopus laevis oocytes. Thus, membrane cholesterol regulates trabecular transduction of mechanical information, with TRPV4 channels mainly located outside the cholesterol-enriched membrane domains. Moreover, the biomechanical milieu itself shapes the lipid content of TM membranes. Diet, cholesterol metabolism, and mechanical stress might modulate the conventional outflow pathway and intraocular pressure in glaucoma and diabetes in part by modulating TM mechanosensing.
format	article
author	Monika Lakk Grace F. Hoffmann Aruna Gorusupudi Eric Enyong Amy Lin Paul S. Bernstein Trine Toft-Bertelsen Nanna MacAulay Michael H. Elliott David Križaj
author_facet	Monika Lakk Grace F. Hoffmann Aruna Gorusupudi Eric Enyong Amy Lin Paul S. Bernstein Trine Toft-Bertelsen Nanna MacAulay Michael H. Elliott David Križaj
author_sort	Monika Lakk
title	Membrane cholesterol regulates TRPV4 function, cytoskeletal expression, and the cellular response to tension
title_short	Membrane cholesterol regulates TRPV4 function, cytoskeletal expression, and the cellular response to tension
title_full	Membrane cholesterol regulates TRPV4 function, cytoskeletal expression, and the cellular response to tension
title_fullStr	Membrane cholesterol regulates TRPV4 function, cytoskeletal expression, and the cellular response to tension
title_full_unstemmed	Membrane cholesterol regulates TRPV4 function, cytoskeletal expression, and the cellular response to tension
title_sort	membrane cholesterol regulates trpv4 function, cytoskeletal expression, and the cellular response to tension
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/ddf84964e0c34f4f9e32ca66ec7cc420
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Membrane cholesterol regulates TRPV4 function, cytoskeletal expression, and the cellular response to tension

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