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Title: The Ca2+-activated cation channel TRPM4 is regulated by phosphatidylinositol 4,5-biphosphate
Authors: Nilius, Bernd ×
Mahieu, Frank
Prenen, Jean
Janssens, Annelies
Owsianik, Grzegorz
Vennekens, Rudi
Voets, Thomas #
Issue Date: Feb-2006
Publisher: Nature Publishing Group
Series Title: EMBO Journal vol:25 issue:3 pages:467-478
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.
URI: 
ISSN: 0261-4189
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Physiology Section (-)
Department of Cellular and Molecular Medicine - miscellaneous
Laboratory of Ion Channel Research
× corresponding author
# (joint) last author

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