Redox signal-mediated sensitization of transient receptor potential melastatin 2 (TRPM2) to temperature affects macrophage functions
Redox signal-mediated sensitization of transient receptor potential melastatin 2 (TRPM2) to temperature affects macrophage functions
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DOI：
10.1073/pnas.1114193109
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发表时间：
2012-04-24
影响因子：
11.1
通讯作者：
Tominaga, Makoto
中科院分区：
文献类型：
--
作者：
Kashio, Makiko;Sokabe, Takaaki;Tominaga, Makoto
感知温度的能力对生物体的生存和有效的新陈代谢至关重要。体温深刻地影响着许多生理功能，包括免疫力。瞬时受体电位美拉抑素2 （TRPM2）是一种热敏、Ca2+渗透的阳离子通道，在多种免疫细胞中表达。TRPM2被二磷酸腺苷核糖和过氧化氢（H2O2）激活，尽管H2O2的激活机制尚不清楚。在这里，我们报告了一种独特的激活机制，其中H2O2通过Met氧化和腺苷二磷酸核糖生成降低TRPM2激活的温度阈值，称为“敏化”。Met-214的单一突变完全消除了这种致敏作用，这表明TRPM2激活的温度阈值是由氧化还原信号调节的，氧化还原信号使通道在生理体温下具有活性。TRPM2的缺失会减弱酶酶引起的巨噬细胞功能，包括细胞因子释放和发热增强的吞噬活性。这些发现表明，氧化还原信号使NADPH氧化酶活性下游的TRPM2增敏，并使TRPM2在生理体温下活跃，导致胞质Ca2+浓度增加。我们的研究结果表明，TRPM2致敏在巨噬细胞功能中起重要作用。
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, Ca2+-permeable cation channel expressed in a wide range of immunocytes. TRPM2 is activated by adenosine diphosphate ribose and hydrogen peroxide (H2O2), although the activation mechanism by H2O2 is not well understood. Here we report a unique activation mechanism in which H2O2 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 Ca2+ concentrations. Our results suggest that TRPM2 sensitization plays important roles in macrophage functions.