Membrane cholesterol regulates TRPV4 function, cytoskeletal expression, and the cellular response to tension
| Autor: | David Križaj, Trine Lisberg Toft-Bertelsen, Michael H. Elliott, Nanna MacAulay, Paul S. Bernstein, Grace F. Hoffmann, Eric Enyong, Aruna Gorusupudi, Amy Lin, Monika Lakk |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
MβCD m-β-cyclodextrin TM trabecular meshwork ROI region of interest Mechanotransduction Cellular Biochemistry [Ca2+]i intracellular calcium concentration TMCM trabecular meshwork cell medium Xenopus laevis Transient receptor potential channel chemistry.chemical_compound Endocrinology Caveolae TRPV4 transient receptor potential vanilloid isoform 4 Mechanotransduction dyslipidemias Cytoskeleton Lipid raft Cells Cultured lipid rafts Chemistry NA numerical aperture Cav-1 caveolin-1 smooth muscle cells ECM extracellular matrix Cell biology αSMA α-smooth muscle actin Cholesterol medicine.anatomical_structure eye/retina lipids (amino acids peptides and proteins) Research Article TRPV4 HTS hypotonic stimuli PBS phosphate-buffered saline TRPV Cation Channels QD415-436 ir immunoreactivity medicine cell signaling Animals Humans mechanotransduction Aged cyclodextrins Cell Membrane Cell Biology Actin cytoskeleton IOP intraocular pressure F-actin filamentous actin glaucoma Tonicity Trabecular meshwork Homeostasis C/PC cholesterol/phosphatidylcholine |
| Zdroj: | Lakk, M, Hoffmann, G F, Gorusupudi, A, Enyong, E, Lin, A, Bernstein, P S, Toft-Bertelsen, T, MacAulay, N, Elliott, M H & Krizaj, D 2021, ' Membrane cholesterol regulates TRPV4 function, cytoskeletal expression, and the cellular response to tension ', Journal of Lipid Research, vol. 62 . https://doi.org/10.1016/j.jlr.2021.100145 Journal of Lipid Research Journal of Lipid Research, Vol 62, Iss, Pp 100145-(2021) |
| DOI: | 10.1016/j.jlr.2021.100145 |
| Popis: | 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. Graphical abstract |
| Databáze: | OpenAIRE |
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