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J. Biol. Chem., Vol. 282, Issue 5, 3325-3336, February 2, 2007

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TRPM8-independent Menthol-induced Ca²⁺ Release from Endoplasmic Reticulum and Golgi^*

From the Department of Molecular Cell Biology, Division of Physiology, Laboratory of Ion Channel Research, KU Leuven, B-3000 Leuven, Belgium

Menthol, a secondary alcohol produced by the peppermint herb, Mentha piperita, is widely used in the food and pharmaceutical industries as a cooling/soothing compound and odorant. It induces Ca²⁺ influx in a subset of sensory neurons from dorsal root and trigeminal ganglia, due to activation of TRPM8, a Ca²⁺-permeable, cold-activated member of the TRP superfamily of cation channels. Menthol also induces Ca²⁺ release from intracellular stores in several TRPM8-expressing cell types, which has led to the suggestion that TRPM8 can function as an intracellular Ca²⁺-release channel. Here we show that menthol induces Ca²⁺ release from intracellular stores in four widely used cell lines (HEK293, lymph node carcinoma of the prostate (LNCaP), Chinese hamster ovary (CHO), and COS), and provide several lines of evidence indicating that this release pathway is TRPM8-independent: 1) menthol-induced Ca²⁺ release was potentiated at higher temperatures, which contrasts to the cold activation of TRPM8; 2) overexpression of TRPM8 did not enhance the menthol-induced Ca²⁺ release; 3) menthol-induced Ca²⁺ release was mimicked by geraniol and linalool, which are structurally related to menthol, but not by the more potent TRPM8 agonists icilin or eucalyptol; and 4) TRPM8 expression in HEK293 cells was undetectable at the protein and mRNA levels. Moreover, using a novel TRPM8-specific antibody we demonstrate that both heterologously expressed TRPM8 (in HEK293 cells) and endogenous TRPM8 (in LNCaP cells) are mainly localized in the plasma membrane, which contrast to previous localization studies using commercial anti-TRPM8 antibodies. Finally, aequorin-based measurements demonstrate that the TRPM8-independent menthol-induced Ca²⁺ release originates from both endoplasmic reticulum and Golgi compartments.

Received for publication, May 31, 2006 , and in revised form, November 10, 2006.

^* This work was supported by Human Frontiers Science Programme Research Grant RGP 32/2004, the Belgian Federal Government, the Flemish Government, Onderzoeksraad KU Leuven Grants GOA 2004/07, F.W.O. G.0136.00; F.W.O. G.0172.03, Interuniversity Poles of Attraction Program, Prime Ministers Office IUAP Nr.3P4/23, and Excellentiefinanciering EF/95/010. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Div. of Physiology, Campus Gasthuisberg, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium. Tel.: 32-16-330217; Fax: 32-16-345991; E-mail: thomas.voets{at}med.kuleuven.be.

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