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.
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.
['Lukacs|Viktor|V|', 'Rives|Jan-Michael|JM|', 'Sun|Xiaohui|X|', 'Zakharian|Eleonora|E|', 'Rohacs|Tibor|T|']
D019870:1-Phosphatidylinositol 4-Kinase D000255:Adenosine Triphosphate D000818:Animals D005260:Female D057809:HEK293 Cells D006801:Humans D008051:Lipid Bilayers D009865:Oocytes D018408:Patch-Clamp Techniques D019269:Phosphatidylinositol 4,5-Diphosphate D018129:Phosphatidylinositol Phosphates D010716:Phosphatidylinositols D054801:Phosphoinositide Phospholipase C D051381:Rats D011994:Recombinant Proteins D050916:TRPV Cation Channels D014982:Xenopus laevis
TRPV1 Phosphoinositides Ion Channels Electrophysiology Inositol Phospholipid TRP Channels