1997 Fiscal Year Final Research Report Summary
Identification of histamine H_1 receptor subtypes
| Project/Area Number |
07557194
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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 | 展開研究 |
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| Research Field |
General pharmacology
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| Research Institution | Osaka University |
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Principal Investigator |
FUKUI Hiroyuki Osaka university, Medical School, Associate Professor, 医学部, 助教授 (90112052)
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| Co-Investigator(Kenkyū-buntansha) |
ONDA Haruo Takeda Pharmaceutical Company, 開拓第一研究所, 部長
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| Project Period (FY) |
1995 – 1997
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| Keywords | histamine / receptor / adrenal medulla / cloning / Xenopus Laevis oocyte |
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| Research Abstract |
mRNA derived from bovine adrenal medulla was fractionated by the sucrose density gradient centrifugation, and each fraction was injected into Xenopus Laevis oocytes. Expression of histamine H_1 receptors was electrophysiologically examined. Injection of fractions containing 3.5-kb mRNA or 5.0-kb mRNA induced the expression of histamine H_1 receptors. This result suggests the existence of histamine H_1 receptor subtypes. Histamine H_1 receptor-dependent inward Cl^- current was aprox. 50nA when 3.5-kb mRNA was injected, and smaller than 40nA when 5.0-kb mRNA was injected. cDNA libraries derived from 3.5-kb mRMA and 5.0-kb mRNA were constructed using lambda ZAPII,a vector for in vitro transcription. The cDNA library was screened by the injection of mRNA through in vitro transcription and electrophysiological detection of histamine H_1 receptor expression. The histamine H_1 receptor cDNA derived from 3.5-kb mRNA was isolated, and the structure of the receptor was determined. The detection of histamine H_1 receptor-dependent inward Cl^- current from 5.0-kb mRNA fraction was not succeeded when mRNA through in vitro transcription was injected. Recently histamine H_1 receptor knock out mouse was prepared, and the lack of histamine H_1 receptors was demonstrated by the autoradiography of [^3H] mepyramine binding. This result indicated that mouse has only one histamine H_1 receptor gene. We observed that human and guinea pig have two kinds of histamine H_1 rceptor mRNAs with different molecular weights. Physiological and pathological roles of histamine differ from species, and the possibility of histamine H_1 receptor subtypes in human and guinea pig still remains.
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[Publications] Fukui, H,Mizuguchi, H,Liu, YQ,Wang, NP,Hayashi, H,Kangawa, K,Wakamiya, T,Leurs, R,Shiba, T and Matsuo, H: "Purification and characterization of [^3H] mepyramine, a histamine H_1 antagonist, binding protein from rat liver : a highly homologous protein with cytochrome P450 2D" J Biochem. 117. 993-998 (1995)
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[Publications] Takagishi, T,Sasaguri, Y,Nakano, R,Arima, N,Tanimoto, A,Fukui, H and Morimatsu, M: "Expression of the histamine H_1 receptor gene in relation to athelosclerosis" Am J Pathol. 146. 981-988 (1995)
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[Publications] Nonaka, H,Otaki, S,Ohshima, E,Kono, M,Kase, H,Ohta, K,Fukui, H and Ichimura, M: "Unique binding pocket for KW-4679 in the histamine H_1 receptor" Eur J Pharmacol. (in press).
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