title: Redox signal-mediated sensitization of transient receptor potential melastatin 2 (TRPM2) to temperature affects macrophage functions.
abstract: The ability to sense temperature is essential for organism survival and efficient metabolism. Body temperatures profoundly affect many physiological functions, including immunity. Transient receptor potential melastatin 2 (TRPM2) is a thermosensitive, Ca(2+)-permeable cation channel expressed in a wide range of immunocytes. TRPM2 is activated by adenosine diphosphate ribose and hydrogen peroxide (H(2)O(2)), although the activation mechanism by H(2)O(2) is not well understood. Here we report a unique activation mechanism in which H(2)O(2) lowers the temperature threshold for TRPM2 activation, termed "sensitization," through Met oxidation and adenosine diphosphate ribose production. This sensitization is completely abolished by a single mutation at Met-214, indicating that the temperature threshold of TRPM2 activation is regulated by redox signals that enable channel activity at physiological body temperatures. Loss of TRPM2 attenuates zymosan-evoked macrophage functions, including cytokine release and fever-enhanced phagocytic activity. These findings suggest that redox signals sensitize TRPM2 downstream of NADPH oxidase activity and make TRPM2 active at physiological body temperature, leading to increased cytosolic Ca(2+) concentrations. Our results suggest that TRPM2 sensitization plays important roles in macrophage functions.
authors.affiliation: Division of Cell Signaling, Okazaki Institute for Integrative Bioscience, National Institutes of Natural Sciences, Okazaki 444-8787, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Kashio
authors.forename: Takaaki
authors.initials: T
authors.lastname: Sokabe
authors.forename: Kenji
authors.initials: K
authors.lastname: Shintaku
authors.forename: Takayuki
authors.initials: T
authors.lastname: Uematsu
authors.forename: Naomi
authors.initials: N
authors.lastname: Fukuta
authors.forename: Noritada
authors.initials: N
authors.lastname: Kobayashi
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Mori
authors.forename: Makoto
authors.initials: M
authors.lastname: Tominaga
mesh_terms: D002460:Cell Line; D051152:Clusterin / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000502:physiology*; D010084:Oxidation-Reduction; D013696:Temperature
chemical_list: D051152:Clusterin