Dual regulation of TRPV1 by phosphoinositides

Viktor Lukacs, Baskaran Thyagarajan, P. Várnai, A. Balla, Tamas Balla, Tibor Rohacs

Research output: Contribution to journalArticle

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Abstract

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 PIP 2 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 and dialysis of PtdIns(4,5)P 2 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)P 2 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.

Original languageEnglish
Pages (from-to)7070-7080
Number of pages11
JournalJournal of Neuroscience
Volume27
Issue number26
DOIs
Publication statusPublished - Jun 27 2007

Fingerprint

Phosphatidylinositol 4,5-Diphosphate
Phosphatidylinositols
Capsaicin
Type C Phospholipases
vanilloid receptor subtype 1
Sirolimus
Ion Channels
Phosphoric Monoester Hydrolases
Dialysis
Phospholipids
Hot Temperature

Keywords

  • Desensitization
  • Phosphoinositides
  • PIP
  • TRP channel
  • TRPV1
  • Vanilloid

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Dual regulation of TRPV1 by phosphoinositides. / Lukacs, Viktor; Thyagarajan, Baskaran; Várnai, P.; Balla, A.; Balla, Tamas; Rohacs, Tibor.

In: Journal of Neuroscience, Vol. 27, No. 26, 27.06.2007, p. 7070-7080.

Research output: Contribution to journalArticle

Lukacs, V, Thyagarajan, B, Várnai, P, Balla, A, Balla, T & Rohacs, T 2007, 'Dual regulation of TRPV1 by phosphoinositides', Journal of Neuroscience, vol. 27, no. 26, pp. 7070-7080. https://doi.org/10.1523/JNEUROSCI.1866-07.2007
Lukacs, Viktor ; Thyagarajan, Baskaran ; Várnai, P. ; Balla, A. ; Balla, Tamas ; Rohacs, Tibor. / Dual regulation of TRPV1 by phosphoinositides. In: Journal of Neuroscience. 2007 ; Vol. 27, No. 26. pp. 7070-7080.
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