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The Journal of Neuroscience, March 21, 2007, 27(12):3347-3355; doi:10.1523/JNEUROSCI.4846-06.2007

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Cellular/Molecular
Modulation of the Cold-Activated Channel TRPM8 by Lysophospholipids and Polyunsaturated Fatty Acids

David A. Andersson,^1,2 Mark Nash,^2,3 and Stuart Bevan^1,2

¹Wolfson Centre for Age-Related Diseases, King's College London, London SE1 1UL, United Kingdom, ²Novartis Institute for Biomedical Sciences, London WC1E 6BS, United Kingdom, and ³Novartis Institute for Biomedical Sciences, Horsham, West Sussex RH12 5AB, United Kingdom

Correspondence should be addressed to David Andersson, Wolfson Centre for Age-Related Diseases, Guy's Campus, King's College London, London SE1 1UL, UK. Email: david.andersson{at}kcl.ac.uk

We investigated the role of phospholipase A₂ (PLA₂) and the effects of PLA₂ products (polyunsaturated fatty acids and lysophospholipids) on the cold-sensitive channel transient receptor potential (melastatin)-8 (TRPM8), heterologously expressed in Chinese hamster ovary cells. TRPM8 responses to cold and the agonist icilin were abolished by inhibitors of the calcium-independent (iPLA₂) form of the enzyme, whereas responses to menthol were less sensitive to iPLA₂ inhibition. Inhibition of PLA₂ similarly abolished the cold responses of the majority of cold-sensitive dorsal root ganglion neurons. The products of PLA₂ had opposing effects on TRPM8. Lysophospholipids (LPLs) (lysophosphatidylcholine, lysophosphatidylinositol, and lysophosphatidylserine) altered the thermal sensitivity of TRPM8, raising the temperature threshold toward normal body temperature. Polyunsaturated fatty acids (PUFAs), such as arachidonic acid, inhibited the activation of TRPM8 by cold, icilin, and menthol. The relative potencies of lysophospholipids and PUFAs are such that lysophosphatidylcholine is able to modulate TRPM8 in the presence of an equimolar concentration of arachidonic acid. Positive modulation by LPLs provides a potential physiological mechanism for sensitizing and activating TRPM8 in the absence of temperature variations.

Key words: TRPM8; phospholipase A2; lysophospholipid; arachidonic acid; menthol; icilin

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Received Nov. 7, 2006; revised Feb. 16, 2007; accepted Feb. 19, 2007.

Correspondence should be addressed to David Andersson, Wolfson Centre for Age-Related Diseases, Guy's Campus, King's College London, London SE1 1UL, UK. Email: david.andersson{at}kcl.ac.uk

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Warming up the Cold Reception at a TRPM8 Function

Wendy Y. W. Cheung, Noo-Rie Ha, Michael W. H. Suen, Chen L. Xu, and Cheng Wei T. Yang
J. Neurosci. 2007 27: 7617-7618. [Full Text]  

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