title: Promiscuous activation of transient receptor potential vanilloid 1 (TRPV1) channels by negatively charged intracellular lipids: the key role of endogenous phosphoinositides in maintaining channel activity.
abstract: The regulation of the heat- and capsaicin-activated transient receptor potential vanilloid 1 (TRPV1) channels by phosphoinositides is controversial. Data in cellular systems support the dependence of TRPV1 activity on phosphoinositides. The purified TRPV1, however, was recently shown to be fully functional in artificial liposomes in the absence of phosphoinositides. Here, we show that several other negatively charged phospholipids, including phosphatidylglycerol, can also support TRPV1 activity in excised patches at high concentrations. When we incorporated TRPV1 into planar lipid bilayers consisting of neutral lipids, capsaicin-induced activity depended on phosphatidylinositol 4,5-bisphosphate. We also found that TRPV1 activity in excised patches ran down and that MgATP reactivated the channel. Inhibition of phosphatidylinositol 4-kinases or enzymatic removal of phosphatidylinositol abolished this effect of MgATP, suggesting that it activated TRPV1 by generating endogenous phosphoinositides. We conclude that endogenous phosphoinositides are positive cofactors for TRPV1 activity. Our data highlight the importance of specificity in lipid regulation of ion channels and may reconcile discordant data obtained in various experimental settings.
authors.affiliation: From the Department of Pharmacology and Physiology, Rutgers New Jersey Medical School, Newark, New Jersey 07103 and.
authors.forename: Viktor
authors.initials: V
authors.lastname: Lukacs
authors.forename: Jan-Michael
authors.initials: JM
authors.lastname: Rives
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Sun
authors.forename: Eleonora
authors.initials: E
authors.lastname: Zakharian
authors.forename: Tibor
authors.initials: T
authors.lastname: Rohacs
mesh_terms: D019870:1-Phosphatidylinositol 4-Kinase / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism*; D054801:Phosphoinositide Phospholipase C / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D050916:TRPV Cation Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D008051:Lipid Bilayers; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols; D011994:Recombinant Proteins; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C037178:phosphatidylinositol 4-phosphate; D000255:Adenosine Triphosphate; D019870:1-Phosphatidylinositol 4-Kinase; D054801:Phosphoinositide Phospholipase C
keywords: Electrophysiology; Inositol Phospholipid; Ion Channels; Phosphoinositides; TRP Channels; TRPV1