Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 17, Pages 6745-6750Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1114193109
Keywords
calcium; immune cells
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Funding
- Japanese Ministry of Education, Culture, Sports, Science and Technology
- Mitsubishi Foundation
- Japan Society for Promotion of Science
- Grants-in-Aid for Scientific Research [23790919, 23249012, 10J03850] Funding Source: KAKEN
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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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