| Project/Area Number |
23659042
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| Research Category |
Grant-in-Aid for Challenging Exploratory Research
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| Allocation Type | Multi-year Fund |
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| Research Field |
Biological pharmacy
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| Research Institution | Kyushu University |
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Principal Investigator |
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| Project Period (FY) |
2011 – 2012
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| Project Status |
Completed (Fiscal Year 2012)
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| Budget Amount *help |
¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2011: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
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| Keywords | シグナル伝達 / イオンチャネル / アミノ酸 / 細胞外マトリクス / カルシウム / 薬学 / 心血管 / 細胞外マトリックス |
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| Research Abstract |
Amino acids in vivo work not only as components of proteins, but also specificligands activating intracellular nutrition signalings. Although collapse of amino acid balance in vivo has been implicated in the development of several diseases, molecular target(s) connecting amino acid imbalance directly to diseases have not been identified. We identified proline-activated cation channel (PRAC), which is directly activated by extracellular matrix-composing amino acids, such as proline, hydroxyproline, alanine, and glycine. We demonstrated that diacylglycerol-activated transient receptor potential canonical (TRPC) channels (TRPC3 and TRPC6) participated as major components of PRAC in primary-cultured cardiomyocytes and cardiac fibroblasts. Deletion of TRPC3 or TRPC6 abolished amino acid-induced cation influx and subsequent increase in intracellular Ca2+concentration. We also found that autophagy was significantly induced in TRPC3- and TRPC6-deficient mouse hearts, and in cardiomyocytes treated with TRPC3/6 inhibitor. These findings strongly suggest that PRAC plays a critical role in protein recycling in the heart. On the other hand, overexpression of TRPC3 and TRPC6 conferred susceptibility to amino acid -induced Ca2+signaling in PRAC-nonexpressing cells. These results strongly suggest that TRPC3/6 heteromultimer channels function as PRAC.
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