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PMID: 17596456 Published · ppublish English Journal Article Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't

Dual regulation of TRPV1 by phosphoinositides.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 27 ·No. 26 ·2007-06-27 ·Pages 7070-80

Lukacs V, Thyagarajan B, Varnai P, Balla A, Balla T, Rohacs T

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 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 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.

MeSH Terms
Animals Calcium Signaling/drug effects,physiology Capsaicin/pharmacology Cell Line Cell Membrane/drug effects,metabolism Enzyme Inhibitors/pharmacology Hot Temperature/adverse effects Humans Neurons, Afferent/drug effects,metabolism Nociceptors/drug effects,metabolism Oocytes Pain/chemically induced,metabolism,physiopathology Phosphatidylinositol 4,5-Diphosphate/metabolism,pharmacology Phosphatidylinositol Phosphates/metabolism Phosphatidylinositols/metabolism,pharmacology Phosphoric Monoester Hydrolases/metabolism,pharmacology Rats TRPV Cation Channels/drug effects,metabolism Type C Phospholipases/antagonists & inhibitors,metabolism Xenopus laevis
Chemicals
Enzyme Inhibitors Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositol Phosphates Phosphatidylinositols TRPV Cation Channels TRPV1 protein, human Phosphoric Monoester Hydrolases Type C Phospholipases Capsaicin
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Lukacs Viktor
Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey 07103, USA.
Thyagarajan Baskaran
Varnai Peter
Balla Andras
Balla Tamas
Rohacs Tibor
References (51)
51 references, click to expand
  1. Spatiotemporal dynamics of inositol 1,4,5-trisphosphate that underlies complex Ca2+ mobilization patterns.
    Science. 1999 May 28;284(5419):1527-30 PMID: 10348740
  2. Vanilloid (Capsaicin) receptors and mechanisms.
    Pharmacol Rev. 1999 Jun;51(2):159-212 PMID: 10353985
  3. Activation of inwardly rectifying K+ channels by distinct PtdIns(4,5)P2 interactions.
    Nat Cell Biol. 1999 Jul;1(3):183-8 PMID: 10559906
  4. Distinct specificities of inwardly rectifying K(+) channels for phosphoinositides.
    J Biol Chem. 1999 Dec 17;274(51):36065-72 PMID: 10593888
  5. Modulation of nucleotide sensitivity of ATP-sensitive potassium channels by phosphatidylinositol-4-phosphate 5-kinase.
    Proc Natl Acad Sci U S A. 2000 Jan 18;97(2):937-41 PMID: 10639183
  6. Structure, function, and control of phosphoinositide-specific phospholipase C.
    Physiol Rev. 2000 Oct;80(4):1291-335 PMID: 11015615
  7. Monitoring agonist-induced phospholipase C activation in live cells by fluorescence resonance energy transfer.
    J Biol Chem. 2001 May 4;276(18):15337-44 PMID: 11152673
  8. Pharmacology of phosphoinositides, regulators of multiple cellular functions.
    Curr Pharm Des. 2001 Apr;7(6):475-507 PMID: 11281854
  9. The vanilloid receptor: a molecular gateway to the pain pathway.
    Annu Rev Neurosci. 2001;24:487-517 PMID: 11283319
  10. Potentiation of capsaicin receptor activity by metabotropic ATP receptors as a possible mechanism for ATP-evoked pain and hyperalgesia.
    Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6951-6 PMID: 11371611
  11. Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition.
    Nature. 2001 Jun 21;411(6840):957-62 PMID: 11418861
  12. Protein kinase C activation potentiates gating of the vanilloid receptor VR1 by capsaicin, protons, heat and anandamide.
    J Physiol. 2001 Aug 1;534(Pt 3):813-25 PMID: 11483711
  13. The complex and intriguing lives of PIP2 with ion channels and transporters.
    Sci STKE. 2001 Dec 04;2001(111):re19 PMID: 11734659
  14. cAMP-dependent protein kinase regulates desensitization of the capsaicin receptor (VR1) by direct phosphorylation.
    Neuron. 2002 Aug 15;35(4):721-31 PMID: 12194871
  15. Dual regulation of voltage-gated calcium channels by PtdIns(4,5)P2.
    Nature. 2002 Oct 31;419(6910):947-52 PMID: 12410316
  16. Topical and peripherally acting analgesics.
    Pharmacol Rev. 2003 Mar;55(1):1-20 PMID: 12615951
  17. A modular PIP2 binding site as a determinant of capsaicin receptor sensitivity.
    Science. 2003 May 23;300(5623):1284-8 PMID: 12764195
  18. Possible involvement of P2Y2 metabotropic receptors in ATP-induced transient receptor potential vanilloid receptor 1-mediated thermal hypersensitivity.
    J Neurosci. 2003 Jul 9;23(14):6058-62 PMID: 12853424
  19. Desensitization of capsaicin-activated currents in the vanilloid receptor TRPV1 is decreased by the cyclic AMP-dependent protein kinase pathway.
    J Biol Chem. 2003 Dec 12;278(50):50080-90 PMID: 14506258
  20. Multiple pools of phosphatidylinositol 4-phosphate detected using the pleckstrin homology domain of Osh2p.
    J Biol Chem. 2004 Oct 22;279(43):44683-9 PMID: 15271978
  21. The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels.
    Nature. 2004 Aug 12;430(7001):748-54 PMID: 15306801
  22. A plasma membrane pool of phosphatidylinositol 4-phosphate is generated by phosphatidylinositol 4-kinase type-III alpha: studies with the PH domains of the oxysterol binding protein and FAPP1.
    Mol Biol Cell. 2005 Mar;16(3):1282-95 PMID: 15635101
  23. Regulation of Ca2+-dependent desensitization in the vanilloid receptor TRPV1 by calcineurin and cAMP-dependent protein kinase.
    J Biol Chem. 2005 Apr 8;280(14):13424-32 PMID: 15691846
  24. A proinflammatory chemokine, CCL3, sensitizes the heat- and capsaicin-gated ion channel TRPV1.
    Proc Natl Acad Sci U S A. 2005 Mar 22;102(12):4536-41 PMID: 15764707
  25. PI(4,5)P2 regulates the activation and desensitization of TRPM8 channels through the TRP domain.
    Nat Neurosci. 2005 May;8(5):626-34 PMID: 15852009
  26. Functional recovery from desensitization of vanilloid receptor TRPV1 requires resynthesis of phosphatidylinositol 4,5-bisphosphate.
    J Neurosci. 2005 May 11;25(19):4835-43 PMID: 15888659
  27. Regulation of ion channels by phosphatidylinositol 4,5-bisphosphate.
    Curr Opin Neurobiol. 2005 Jun;15(3):370-8 PMID: 15922587
  28. Phospholipase C in living cells: activation, inhibition, Ca2+ requirement, and regulation of M current.
    J Gen Physiol. 2005 Sep;126(3):243-62 PMID: 16129772
  29. Phosphatidylinositol 4,5-bisphosphate rescues TRPM4 channels from desensitization.
    J Biol Chem. 2005 Nov 25;280(47):39185-92 PMID: 16186107
  30. Membrane phosphoinositides control insulin secretion through their effects on ATP-sensitive K+ channel activity.
    Diabetes. 2005 Oct;54(10):2852-2858 PMID: 16186385
  31. NGF rapidly increases membrane expression of TRPV1 heat-gated ion channels.
    EMBO J. 2005 Dec 21;24(24):4211-23 PMID: 16319926
  32. Downregulation of transient receptor potential melastatin 8 by protein kinase C-mediated dephosphorylation.
    J Neurosci. 2005 Dec 7;25(49):11322-9 PMID: 16339027
  33. The Ca2+-activated cation channel TRPM4 is regulated by phosphatidylinositol 4,5-biphosphate.
    EMBO J. 2006 Feb 8;25(3):467-78 PMID: 16424899
  34. TRP channels and lipids: from Drosophila to mammalian physiology.
    J Physiol. 2007 Jan 1;578(Pt 1):9-24 PMID: 16990401
  35. Rapid chemically induced changes of PtdIns(4,5)P2 gate KCNQ ion channels.
    Science. 2006 Dec 1;314(5804):1454-7 PMID: 16990515
  36. Regulation of TRP channels by PIP(2).
    Pflugers Arch. 2007 Mar;453(6):753-62 PMID: 17031667
  37. Why pain gets worse: the mechanism of heat hyperalgesia.
    J Gen Physiol. 2006 Nov;128(5):491-3 PMID: 17074974
  38. Phosphoinositide 3-kinase binds to TRPV1 and mediates NGF-stimulated TRPV1 trafficking to the plasma membrane.
    J Gen Physiol. 2006 Nov;128(5):509-22 PMID: 17074976
  39. Rapidly inducible changes in phosphatidylinositol 4,5-bisphosphate levels influence multiple regulatory functions of the lipid in intact living cells.
    J Cell Biol. 2006 Nov 6;175(3):377-82 PMID: 17088424
  40. Modulation of TRPs by PIPs.
    J Physiol. 2007 Aug 1;582(Pt 3):939-44 PMID: 17395625
  41. Regulation of transient receptor potential (TRP) channels by phosphoinositides.
    Pflugers Arch. 2007 Oct;455(1):157-68 PMID: 17479281
  42. A wortmannin-sensitive phosphatidylinositol 4-kinase that regulates hormone-sensitive pools of inositolphospholipids.
    Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5317-21 PMID: 7777504
  43. Regulation of cardiac Na+,Ca2+ exchange and KATP potassium channels by PIP2.
    Science. 1996 Aug 16;273(5277):956-9 PMID: 8688080
  44. Inhibition of calcineurin inhibits the desensitization of capsaicin-evoked currents in cultured dorsal root ganglion neurones from adult rats.
    Pflugers Arch. 1996 Apr;431(6):828-37 PMID: 8927498
  45. Anionic phospholipids activate ATP-sensitive potassium channels.
    J Biol Chem. 1997 Feb 28;272(9):5388-95 PMID: 9038137
  46. The role of calcium in the desensitization of capsaicin responses in rat dorsal root ganglion neurons.
    J Neurosci. 1997 May 15;17(10):3525-37 PMID: 9133377
  47. The capsaicin receptor: a heat-activated ion channel in the pain pathway.
    Nature. 1997 Oct 23;389(6653):816-24 PMID: 9349813
  48. Phosphoinositide kinases.
    Annu Rev Biochem. 1998;67:481-507 PMID: 9759495
  49. The cloned capsaicin receptor integrates multiple pain-producing stimuli.
    Neuron. 1998 Sep;21(3):531-43 PMID: 9768840
  50. Visualization of phosphoinositides that bind pleckstrin homology domains: calcium- and agonist-induced dynamic changes and relationship to myo-[3H]inositol-labeled phosphoinositide pools.
    J Cell Biol. 1998 Oct 19;143(2):501-10 PMID: 9786958
  51. PIP2 and PIP as determinants for ATP inhibition of KATP channels.
    Science. 1998 Nov 6;282(5391):1141-4 PMID: 9804555
Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.1866-07.2007
Published
2007-06-27
Pages
7070-80
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6672228
Subset
IM
Grants
NINDS NIH HHS · R01 NS055159 · United States
Intramural NIH HHS · United States
External Links
PubMed source DOI: 10.1523/JNEUROSCI.1866-07.2007 PMC Full Text View journal details
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