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

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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.