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PNAS:过氧化氢调控TRPM2激活免疫巨噬细胞

来源:生物谷 2012-04-10 10:25

近日,过氧化氢调控的温度传感器开关TRPM2的分子机制已澄清

巨噬细胞在免疫系统防御病原体等外来入侵物质正发挥重要作用。感染发生后,巨噬细胞产生活性氧进行清除异物。然而该机制与温度传感器之间的关系仍不明确。

国家自然科学研究院国家生理科学研究所(冈崎为一体的生物科技研究所)Makoto TOMINAGA教授和他的研究小组成员Makiko KASHIO女士一起确定了其中机制,即体温通过过氧化氢(一种活性氧)激活TRPM2,进而产生免疫反应。这项研究结果发表在PNAS杂志上。

该研究小组集中研究双氧水和TRPM2之间的关系。虽然通常在缺乏内源性配体的情况下,近48摄氏度的高温会激活TRPM2,但我们的正常体温用双氧水也会激活TRPM2。这意味着,过氧化氢能作为控制TRPM2功能的“开关”。此外他们还发现在发热温度(38.5℃)下,巨噬细胞的吞噬活性增强。

新发现的这种TRPM2调控机制可能会导致开发出治疗感染的新药物。当我们感染细菌后,我们经常发烧,而体温对我们免疫系统至关重要。TRPM2或许可以解释发烧增强我们的免疫系统的机制。(生物谷:Bioon)

Redox signal-mediated sensitization of transient receptor potential melastatin 2 (TRPM2) to temperature affects macrophage functions

Makiko Kashioa, Takaaki Sokabea, Kenji Shintakua,b, Takayuki Uematsuc, Naomi Fukutaa, Noritada Kobayashic, Yasuo Morid, and Makoto Tominagaa,b,1

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.

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