| Project/Area Number |
16590719
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Yokohama City University (2006-2007)
Nippon Medical School (2004-2005) |
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Principal Investigator |
OKUMURA Satoshi Yokohama City University, Graduate School of Medicine, Associate Professor (60233475)
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| Co-Investigator(Kenkyū-buntansha) |
ISHIKAWA Tfbshihiro Yokohama City University, Graduate School of Medicine, Professor (40305470)
SATO Naoki Nippon Medical School, 医学部, Assitant Professor (70291721)
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| Project Period (FY) |
2004 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥3,840,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥240,000)
Fiscal Year 2007: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2006: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2005: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2004: ¥1,000,000 (Direct Cost: ¥1,000,000)
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| Keywords | adenylyl cyclase / knockout mouse / isoproterenol / desensitization / mRNA / 5型アデニル酸シクラーゼ / アポトーシス / アデニル酸シクラーゼアッセイ / ベータアドレナリン受容体 / PDK-1 |
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| Research Abstract |
Desensitization of the cAMP signal is a protective mechanism against catecholamine stress on cardiac myocytes to prevent the development of apoptosis. Molecular mechanisms of desensitization have been well studied at the level of receptors, but poorly at the level of the effector enzyme, adenylyl cyclase. To examine the role of type 5 adenylyl cyclase (AC), a major cardiac isoform, in desensitization and apoptosis, we examined the effects of chronic isoproterenol (ISO) infusion in type 5 adenylyl cyclase-null mice (AC5KO) and wild type controls (WT) Desensitization was more effective in AC5KO after infusion, as reflected by a greater degree of downregulation of AC catalytic activity after infusion. WT showed resistance to such desensitization because the type 5 isoform protein expression underwent paradoxical upregulation. The number of apoptotic myocytes was similar at baseline, but significantly smaller in AC5KO after infusion. This was accompanied by a 4-fold greater increase in Bcl-2 and a 3-fold greater increase in phospho-Akt in AC5KO. The latter is most likely through increased membrane localization of PDK1 (phosphoinositide-dependent protein kinase 1), which is known to be inhibited by the CAMP signal. Thus, the property of AC5KO, i.e., enhanced desensitization and protection against apoptosis, suggests that isoform-specific inhibition of type 5 AC may be beneficial following chronic catecholamine stress, and potentially in the treatment of heart failure.
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