2023 Fiscal Year Final Research Report
Physiological roles of TRPM2 associating body temperature and metabolism
| Project/Area Number |
20K06748
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 44050:Animal physiological chemistry, physiology and behavioral biology-related
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| Research Institution | National Institute for Physiological Sciences (2021-2023)
Aichi Medical University (2020) |
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Principal Investigator |
Kashio Makiko 生理学研究所, 生体機能調節研究領域, 特任准教授 (20631394)
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| Project Period (FY) |
2020-04-01 – 2024-03-31
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| Keywords | TRPM2 / 体温 / リン酸化 |
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| Outline of Final Research Achievements |
Transient receptor potential melastatin type 2 (TRPM2) is a non-selective cation channel with sensitivity to warm temperature. This study has revealed one molecular mechanism regulating TRPM2 activity at body temperature mediated by cytosolic Ca2+ and TRPM2 phosphorylation by protein kinase C activity. Cytosolic Ca2+ decreases temperature threshold for TRPM2 activation in concentration-dependent manner. TRPM2 phosphorylation counteracts the effect of cytosolic Ca2+ to decrease temperature threshold for TRPM2 activation. Alanine-scan mutagenesis identified a candidate threonine residue (Thr738) and its phospho-deficient mutation (T738A) abrogated the effect of PKC on temperature threshold for TRPM2. Moreover, phospho-mimic mutation (T738D) recapitulated the effect of PKC, confirming the roles of Thr738 phosphorylation regulating temperature threshold for TRPM2. The findings in this study could propel elucidation of machinery enabling temperature-dependent activation of TRP channels.
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| Free Research Field |
生理学
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| Academic Significance and Societal Importance of the Research Achievements |
温度感受性TRPM2は、脳、免疫細胞、膵臓等の体温下に保たれた広範な組織に発現しており、免疫機能やインスリン分泌調節への関わりが明らかになっている。一方で、過剰なTRPM2活性は細胞死や炎症を増悪させることも数多く報告されており、生理的環境においてTRPM2体温下活性が適切に調節されることで種々生理機能に寄与していると考えられる。生理的環境で変動しうる細胞内Ca2+とPKC活性によって体温下TRPM2活性が制御されることを示した本研究成果は、TRPM2機能の関わる生理機能・病態生理の解明、さらには温度によるTRPチャネル活性化の分子基盤の解明につながることが期待される。
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