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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Autor*in:	Monika Lakk [verfasserIn] Grace F. Hoffmann [verfasserIn] Aruna Gorusupudi [verfasserIn] Eric Enyong [verfasserIn] Amy Lin [verfasserIn] Paul S. Bernstein [verfasserIn] Trine Toft-Bertelsen [verfasserIn] Nanna MacAulay [verfasserIn] Michael H. Elliott [verfasserIn] David Križaj [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2021

Schlagwörter:	cell signaling cyclodextrins dyslipidemias eye/retina glaucoma lipid rafts

Übergeordnetes Werk:	In: Journal of Lipid Research - Elsevier, 2021, 62(2021), Seite 100145-
Übergeordnetes Werk:	volume:62 ; year:2021 ; pages:100145-

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1016/j.jlr.2021.100145

Katalog-ID:	DOAJ016512197

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520			\|a 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.
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callnumber-first	Q - Science
author	Monika Lakk
spellingShingle	Monika Lakk misc QD415-436 misc cell signaling misc cyclodextrins misc dyslipidemias misc eye/retina misc glaucoma misc lipid rafts misc Biochemistry Membrane cholesterol regulates TRPV4 function, cytoskeletal expression, and the cellular response to tension
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topic_title	QD415-436 Membrane cholesterol regulates TRPV4 function, cytoskeletal expression, and the cellular response to tension cell signaling cyclodextrins dyslipidemias eye/retina glaucoma lipid rafts
topic	misc QD415-436 misc cell signaling misc cyclodextrins misc dyslipidemias misc eye/retina misc glaucoma misc lipid rafts misc Biochemistry
topic_unstemmed	misc QD415-436 misc cell signaling misc cyclodextrins misc dyslipidemias misc eye/retina misc glaucoma misc lipid rafts misc Biochemistry
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title	Membrane cholesterol regulates TRPV4 function, cytoskeletal expression, and the cellular response to tension
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title_sort	membrane cholesterol regulates trpv4 function, cytoskeletal expression, and the cellular response to tension
callnumber	QD415-436
title_auth	Membrane cholesterol regulates TRPV4 function, cytoskeletal expression, and the cellular response to tension
abstract	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.
abstractGer	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.
abstract_unstemmed	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.
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title_short	Membrane cholesterol regulates TRPV4 function, cytoskeletal expression, and the cellular response to tension
url	https://doi.org/10.1016/j.jlr.2021.100145 https://doaj.org/article/ddf84964e0c34f4f9e32ca66ec7cc420 http://www.sciencedirect.com/science/article/pii/S0022227521001279 https://doaj.org/toc/0022-2275
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author2	Grace F. Hoffmann Aruna Gorusupudi Eric Enyong Amy Lin Paul S. Bernstein Trine Toft-Bertelsen Nanna MacAulay Michael H. Elliott David Križaj
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up_date	2024-07-03T21:28:26.739Z
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Membrane cholesterol regulates TRPV4 function, cytoskeletal expression, and the cellular response to tension

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