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PMID: 16424899 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

The Ca2+-activated cation channel TRPM4 is regulated by phosphatidylinositol 4,5-biphosphate.

The EMBO journal ·Vol. 25 ·No. 3 ·2006-02-08 ·Pages 467-78

Nilius B, Mahieu F, Prenen J, Janssens A, Owsianik G, Vennekens R, Voets T

Abstract

Transient receptor potential (TRP) channel, melastatin subfamily (TRPM)4 is a Ca2+-activated monovalent cation channel that depolarizes the plasma membrane and thereby modulates Ca2+ influx through Ca2+-permeable pathways. A typical feature of TRPM4 is its rapid desensitization to intracellular Ca2+ ([Ca2+]i). Here we show that phosphatidylinositol 4,5-biphosphate (PIP2) counteracts desensitization to [Ca2+]i in inside-out patches and rundown of TRPM4 currents in whole-cell patch-clamp experiments. PIP2 shifted the voltage dependence of TRPM4 activation towards negative potentials and increased the channel's Ca2+ sensitivity 100-fold. Conversely, activation of the phospholipase C (PLC)-coupled M1 muscarinic receptor or pharmacological depletion of cellular PIP2 potently inhibited currents through TRPM4. Neutralization of basic residues in a C-terminal pleckstrin homology (PH) domain accelerated TRPM4 current desensitization and strongly attenuated the effect of PIP2, whereas mutations to the C-terminal TRP box and TRP domain had no effect on the PIP2 sensitivity. Our data demonstrate that PIP2 is a strong positive modulator of TRPM4, and implicate the C-terminal PH domain in PIP2 action. PLC-mediated PIP2 breakdown may constitute a physiologically important brake on TRPM4 activity.

MeSH Terms
Amino Acid Sequence Animals Calcium/metabolism Cell Line Cell Membrane/physiology Cricetinae Cricetulus Humans Ion Channel Gating Molecular Sequence Data Mutation Patch-Clamp Techniques Phosphatidylinositol 4,5-Diphosphate/physiology Protein Structure, Tertiary Receptor, Muscarinic M1/genetics,physiology TRPM Cation Channels/genetics,physiology Type C Phospholipases/metabolism
Chemicals
Phosphatidylinositol 4,5-Diphosphate Receptor, Muscarinic M1 TRPM Cation Channels TRPM4 protein, human Type C Phospholipases Calcium
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Nilius Bernd
Department of Physiology, Campus Gasthuisberg, KU Leuven, Leuven, Belgium. bernd.nilius@med.kuleuven.ac.be
Mahieu Frank
Prenen Jean
Janssens Annelies
Owsianik Grzegorz
Vennekens Rudi
Voets Thomas
References (37)
37 references, click to expand
  1. PIP2 increases the speed of response of synaptotagmin and steers its membrane-penetration activity toward the plasma membrane.
    Nat Struct Mol Biol. 2004 Jan;11(1):36-44 PMID: 14718921
  2. Phosphatidylinositol 4,5-bisphosphate rescues TRPM4 channels from desensitization.
    J Biol Chem. 2005 Nov 25;280(47):39185-92 PMID: 16186107
  3. Antagonist binding properties of five cloned muscarinic receptors expressed in CHO-K1 cells.
    Mol Pharmacol. 1989 Apr;35(4):469-76 PMID: 2704370
  4. Site-directed mutagenesis by overlap extension using the polymerase chain reaction.
    Gene. 1989 Apr 15;77(1):51-9 PMID: 2744487
  5. Receptor-coupled signal transduction in human polymorphonuclear neutrophils: effects of a novel inhibitor of phospholipase C-dependent processes on cell responsiveness.
    J Pharmacol Exp Ther. 1990 May;253(2):688-97 PMID: 2338654
  6. Selective inhibition of receptor-coupled phospholipase C-dependent processes in human platelets and polymorphonuclear neutrophils.
    J Pharmacol Exp Ther. 1990 Nov;255(2):756-68 PMID: 2147038
  7. Pleckstrin homology domains bind to phosphatidylinositol-4,5-bisphosphate.
    Nature. 1994 Sep 8;371(6493):168-70 PMID: 8072546
  8. 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
  9. Decavanadate modulates gating of TRPM4 cation channels.
    J Physiol. 2004 Nov 1;560(Pt 3):753-65 PMID: 15331675
  10. TRPM4 regulates calcium oscillations after T cell activation.
    Science. 2004 Nov 19;306(5700):1374-7 PMID: 15550671
  11. Phosphatidylinositol [correction] 4,5-bisphosphate signals underlie receptor-specific Gq/11-mediated modulation of N-type Ca2+ channels.
    J Neurosci. 2004 Dec 1;24(48):10980-92 PMID: 15574748
  12. Comparison of functional properties of the Ca2+-activated cation channels TRPM4 and TRPM5 from mice.
    Cell Calcium. 2005 Mar;37(3):267-78 PMID: 15670874
  13. Regulation of Drosophila transient receptor potential-like (TrpL) channels by phospholipase C-dependent mechanisms.
    J Physiol. 2001 Jan 1;530(Pt 1):1-19 PMID: 11136854
  14. Functional control of cold- and menthol-sensitive TRPM8 ion channels by phosphatidylinositol 4,5-bisphosphate.
    J Neurosci. 2005 Feb 16;25(7):1674-81 PMID: 15716403
  15. Regulation of the Ca2+ sensitivity of the nonselective cation channel TRPM4.
    J Biol Chem. 2005 Feb 25;280(8):6423-33 PMID: 15590641
  16. PIP2 hydrolysis underlies agonist-induced inhibition and regulates voltage gating of two-pore domain K+ channels.
    J Physiol. 2005 Apr 1;564(Pt 1):117-29 PMID: 15677683
  17. 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
  18. Disruption of the mouse inositol 1,3,4,5,6-pentakisphosphate 2-kinase gene, associated lethality, and tissue distribution of 2-kinase expression.
    Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8448-53 PMID: 15939868
  19. Regulation of ion channels by phosphatidylinositol 4,5-bisphosphate.
    Curr Opin Neurobiol. 2005 Jun;15(3):370-8 PMID: 15922587
  20. Gating of TRP channels: a voltage connection?
    J Physiol. 2005 Aug 15;567(Pt 1):35-44 PMID: 15878939
  21. Pharmacology of phosphoinositides, regulators of multiple cellular functions.
    Curr Pharm Des. 2001 Apr;7(6):475-507 PMID: 11281854
  22. Calcium influx via TRP channels is required to maintain PIP2 levels in Drosophila photoreceptors.
    Neuron. 2001 Apr;30(1):149-59 PMID: 11343651
  23. 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
  24. The complex and intriguing lives of PIP2 with ion channels and transporters.
    Sci STKE. 2001 Dec 4;2001(111):re19 PMID: 11734659
  25. Phosphoinositide-specific inositol polyphosphate 5-phosphatase IV inhibits Akt/protein kinase B phosphorylation and leads to apoptotic cell death.
    J Biol Chem. 2002 Feb 22;277(8):6266-72 PMID: 11706019
  26. PIP(2) and proteins: interactions, organization, and information flow.
    Annu Rev Biophys Biomol Struct. 2002;31:151-75 PMID: 11988466
  27. The TRPM7 channel is inactivated by PIP(2) hydrolysis.
    Nat Cell Biol. 2002 May;4(5):329-36 PMID: 11941371
  28. TRPM4 is a Ca2+-activated nonselective cation channel mediating cell membrane depolarization.
    Cell. 2002 May 3;109(3):397-407 PMID: 12015988
  29. Alterations in conserved Kir channel-PIP2 interactions underlie channelopathies.
    Neuron. 2002 Jun 13;34(6):933-44 PMID: 12086641
  30. Dual regulation of voltage-gated calcium channels by PtdIns(4,5)P2.
    Nature. 2002 Oct 31;419(6910):947-52 PMID: 12410316
  31. PIP(2) activates KCNQ channels, and its hydrolysis underlies receptor-mediated inhibition of M currents.
    Neuron. 2003 Mar 27;37(6):963-75 PMID: 12670425
  32. A modular PIP2 binding site as a determinant of capsaicin receptor sensitivity.
    Science. 2003 May 23;300(5623):1284-8 PMID: 12764195
  33. TRPM5 is a voltage-modulated and Ca(2+)-activated monovalent selective cation channel.
    Curr Biol. 2003 Jul 1;13(13):1153-8 PMID: 12842017
  34. Voltage dependence of the Ca2+-activated cation channel TRPM4.
    J Biol Chem. 2003 Aug 15;278(33):30813-20 PMID: 12799367
  35. Intracellular Ca2+ and the phospholipid PIP2 regulate the taste transduction ion channel TRPM5.
    Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15160-5 PMID: 14657398
  36. PIP2 activates TRPV5 and releases its inhibition by intracellular Mg2+.
    J Gen Physiol. 2005 Nov;126(5):439-51 PMID: 16230466
  37. The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels.
    Nature. 2004 Aug 12;430(7001):748-54 PMID: 15306801
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1038/sj.emboj.7600963
Email
bernd.nilius@med.kuleuven.ac.be
Published
2006-02-08
Epub
2006-00-19
Pages
467-78
Language
English
Region
England
NLM ID
8208664
PMCID
PMC1383543
Subset
IM
External Links
PubMed source DOI: 10.1038/sj.emboj.7600963 PMC Full Text View journal details
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