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The Ca 2+ ‐activated cation channel TRPM4 is regulated by phosphatidylinositol 4,5‐biphosphate
Author(s) -
Nilius Bernd,
Mahieu Frank,
Prenen Jean,
Janssens Annelies,
Owsianik Grzegorz,
Vennekens Rudi,
Voets Thomas
Publication year - 2006
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600963
Subject(s) - biology , phosphatidylinositol , transient receptor potential channel , biochemistry , biophysics , microbiology and biotechnology , signal transduction , receptor
Transient receptor potential (TRP) channel, melastatin subfamily (TRPM)4 is a Ca 2+ ‐activated monovalent cation channel that depolarizes the plasma membrane and thereby modulates Ca 2+ influx through Ca 2+ ‐permeable pathways. A typical feature of TRPM4 is its rapid desensitization to intracellular Ca 2+ ([Ca 2+ ] i ). Here we show that phosphatidylinositol 4,5‐biphosphate (PIP 2 ) counteracts desensitization to [Ca 2+ ] i in inside‐out patches and rundown of TRPM4 currents in whole‐cell patch‐clamp experiments. PIP 2 shifted the voltage dependence of TRPM4 activation towards negative potentials and increased the channel's Ca 2+ sensitivity 100‐fold. Conversely, activation of the phospholipase C (PLC)‐coupled M1 muscarinic receptor or pharmacological depletion of cellular PIP 2 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 PIP 2 , whereas mutations to the C‐terminal TRP box and TRP domain had no effect on the PIP 2 sensitivity. Our data demonstrate that PIP 2 is a strong positive modulator of TRPM4, and implicate the C‐terminal PH domain in PIP 2 action. PLC‐mediated PIP 2 breakdown may constitute a physiologically important brake on TRPM4 activity.