The Ca 2+ ‐activated cation channel TRPM4 is regulated by phosphatidylinositol 4,5‐biphosphate

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.