2004 Fiscal Year Final Research Report Summary
Mechanisms on constitutive activation of receptors and inverse agonists
| Project/Area Number |
14370030
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General pharmacology
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| Research Institution | University of Fukui (2004)
福井医科大学 (2002-2003) |
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Principal Investigator |
MARUMATSU Ikunobu University of Fukui, Faculty of Medical Sciences, Professor, 医学部, 教授 (10111965)
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| Co-Investigator(Kenkyū-buntansha) |
SUZUKI Fumiko University of Fukui, Faculty of Medical Sciences, Assistant Professor, 医学部, 助手 (80291376)
TANAKA Takashi University of Fukui, Faculty of Medical Sciences, Assistant Professor, 医学部, 助手 (40313746)
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| Project Period (FY) |
2002 – 2004
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| Keywords | receptor (alpha-1 adrenoceptor) / snapin / constitutive activity / inverse agonist / heterodimer / supersensitivity |
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| Research Abstract |
Many receptors are constitutively active in the absence of agonists. In this research, mechanisms on constitutive activation and the in vivo effects of inverse agonist were examined in the case of alpha-1 adrenoceptors.
1.In yeast two hybridization study, 3 proteins associated with alpha-1 adrenoceptor were identified. One is snapin, which interacted with C-terminal of alpha-1 adrenoceptor. Co-expression of alpha-1 adrenoceptor and snap in in PC 12 cells produced an augmentation of dopamine release upon methoxamine stimulation. However, no constitutive activity of alpha-1 adrenoceptor was produced by co-expression with snapin.
2.Co-expression of alpha-1A and alpha-1B adrenoceptors in HEK 293 cells produced supersensitivity and augmentation of maximum response in response to phenylephrine but not to methoxamine, suggesting the presence of hetero-dimerization and crosstalk between two subtypes. However, constitutive activation was caused by the hetero-dimerization.
3.Chronic administration of an inverse agonist prazosin produced supersensitivity in the adrenergic contractions induced by phenylephrine and electrical transmural stimulation in rat tail artery, which was related to the switching of functional adrenoceptor from alpha-1A subtype to alpha-1B subtype. On the other hand, an alpha-1A selective and neutral antagonist KMD-3213 failed to cause supersensitity in the adrenergic responses of rat tail artery.
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Research Products
(36 results)
