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The Journal of Neuroscience, June 27, 2007, 27(26):7070-7080; doi:10.1523/JNEUROSCI.1866-07.2007

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 Previous Article

Cellular/Molecular
Dual Regulation of TRPV1 by Phosphoinositides

Viktor Lukacs,^1 * Baskaran Thyagarajan,^1 * Peter Varnai,² Andras Balla,² Tamas Balla,² and Tibor Rohacs¹

¹Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey–New Jersey Medical School, Newark, New Jersey 07103, and ²Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892

Correspondence should be addressed to Dr. Tibor Rohacs, Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey–New Jersey Medical School, 185 South Orange Avenue, MSB H631, Newark, NJ 07103. Email: tibor.rohacs{at}umdnj.edu

The membrane phospholipid phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P₂ or PIP₂] regulates many ion channels. There are conflicting reports on the effect of PtdIns(4,5)P₂ on transient receptor potential vanilloid 1 (TRPV1) channels. We show that in excised patches PtdIns(4,5)P₂ and other phosphoinositides activate and the PIP₂ scavenger poly-Lys inhibits TRPV1. TRPV1 currents undergo desensitization on exposure to high concentrations of capsaicin in the presence of extracellular Ca²⁺. We show that in the presence of extracellular Ca²⁺, capsaicin activates phospholipase C (PLC) in TRPV1-expressing cells, inducing depletion of both PtdIns(4,5)P₂ and its precursor PtdIns(4)P (PIP). The PLC inhibitor U73122 [GenBank] and dialysis of PtdIns(4,5)P₂ or PtdIns(4)P through the patch pipette inhibited desensitization of TRPV1, indicating that Ca²⁺-induced activation of PLC contributes to desensitization of TRPV1 by depletion of PtdIns(4,5)P₂ and PtdIns(4)P. Selective conversion of PtdIns(4,5)P₂ to PtdIns(4)P by a rapamycin-inducible PIP₂ 5-phosphatase did not inhibit TRPV1 at high capsaicin concentrations, suggesting a significant role for PtdIns(4)P in maintaining channel activity. Currents induced by low concentrations of capsaicin and moderate heat, however, were potentiated by conversion of PtdIns(4,5)P₂ to PtdIns(4)P. Increasing PtdIns(4,5)P₂ levels by coexpressing phosphatidylinositol-4-phosphate 5-kinase inhibited TRPV1 at low but not at saturating capsaicin concentrations. These data show that at low capsaicin concentrations and other moderate stimuli, PtdIns(4,5)P₂ partially inhibits TRPV1 in a cellular context, but this effect is likely to be indirect, because it is not detectable in excised patches. We conclude that phosphoinositides have both inhibitory and activating effects on TRPV1, resulting in complex and distinct regulation at various stimulation levels.

Key words: TRPV1; TRP channel; phosphoinositides; PIP₂; vanilloid; desensitization

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Received Dec. 1, 2006; revised May 23, 2007; accepted May 24, 2007.

Correspondence should be addressed to Dr. Tibor Rohacs, Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey–New Jersey Medical School, 185 South Orange Avenue, MSB H631, Newark, NJ 07103. Email: tibor.rohacs{at}umdnj.edu

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