In 1950, Hensel and Zotterman reported cooling-induced desensitization of cold receptors by extracellular discharge recordings of cold fibers. Since then, however, its intracellular mechanism has remained unresolved. We studied menthol-induced desensitization of cold/menthol receptors (TRPM8, transient receptor potential M8) expressed in HEK cells. TRPM8 desensitization depended on extracellular Ca2+ ions, indicating that Ca2+ influx-induced [Ca2+]i elevation caused the desensitization. We studied whether Ca2+-dependent kinase, PKC, mediated TRPM8 desensitization. PMA, a PKC activator, desensitized TRPM8. Inhibitor of Ca2+-dependent PKC isozymes specifically abolished PMA-induced TRPM8 desensitization. PMA similarly desensitized wild type TRPM8 and mutant TRPM8, in which serine or threonine residues in some putative PKC phosphorylation sites were replaced by alanine. PMA treatment did not induce internalization of TRPM8. As the basis of cooling-induced desensitization of cold receptors, we conclude that cooling-activated TRPM8 causes Ca2+-dependent PKC isozymes to desensitize TRPM8 itself.