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The Journal of Neuroscience, February 16, 2005, 25(7):1674-1681; doi:10.1523/JNEUROSCI.3632-04.2005

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Cellular/Molecular
Functional Control of Cold- and Menthol-Sensitive TRPM8 Ion Channels by Phosphatidylinositol 4,5-Bisphosphate

Beiying Liu and Feng Qin

Department of Physiology and Biophysical Sciences, State University of New York at Buffalo, Buffalo, New York 14214

Cold is detected by a small subpopulation of peripheral thermoreceptors. TRPM8, a cloned menthol- and cold-sensitive ion channel, has been suggested to mediate cold transduction in the innocuous range. The channel shows a robust response in whole-cell recordings but exhibits markedly reduced activity in excised membrane patches. Here we report that phosphatidylinositol 4,5-bisphosphate (PIP₂) is an essential regulator of the channel function. The rundown of the channel is prevented by lipid phosphatase inhibitors. Application of exogenous PIP₂ both activates the channel directly and restores rundown activity. Whole-cell experiments involving intracellular dialysis with polyvalent cations, inhibition of PIP₂ synthesis kinases, and receptor-mediated hydrolysis of PIP₂ show that PIP₂ also modulates the channel activity in the intact cells. The crucial role of PIP₂ on the function of TRPM8 suggests that the membrane PIP₂ level may be an important regulator of cold transduction in vivo. The opposite effects of PIP₂ on the vanilloid receptor TRPV1 and TRPM8 also implies that the membrane lipid may have dual actions as a bimodal switch to selectively control the heat- and cold-induced responses in nociceptors expressing both channels.

Key words: cold; menthol; temperature; pain; TRP channels; sensory neurons

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Received Sep 2, 2004; revised January 3, 2005; accepted January 5, 2005.

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