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Inactive Ca2+/calmodulin-dependent protein kinase IIα knockin animal and knockin cell of the same

外国特許コード F110003168
整理番号 A141-05WO
掲載日 2011年6月17日
出願国 アメリカ合衆国
出願番号 59946005
公報番号 20070050858
公報番号 9347936
出願日 平成17年3月24日(2005.3.24)
公報発行日 平成19年3月1日(2007.3.1)
公報発行日 平成28年5月24日(2016.5.24)
国際出願番号 JP2005005350
国際公開番号 WO2005093051
国際出願日 平成17年3月24日(2005.3.24)
国際公開日 平成17年10月6日(2005.10.6)
優先権データ
  • 特願2004-096995 (2004.3.29) JP
  • 特願2004-380376 (2004.12.28) JP
  • 2005JP005350 (2005.3.24) WO
発明の名称 (英語) Inactive Ca2+/calmodulin-dependent protein kinase IIα knockin animal and knockin cell of the same
発明の概要(英語) The present invention provides an inactive Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα) knockin animal in which only the protein kinase activity of CaMKIIα has been specifically impaired.
Since CaMKIIα is considered to be involved in higher brain functions including learning and memory, and inhibit epileptic seizure and brain disorders caused by ischemia, the inactive CaMKIIα knockin animal of the present invention is widely usable for various studies of the brain and nerve, such as the studies of mechanisms of learning disability, dysmnesia, epileptic seizure and brain disorders.
従来技術、競合技術の概要(英語) BACKGROUND ART
Ca2+/calmodulin-dependent protein kinase II (CaMKII) is present abundantly in the central nervous system.
CaMKII is deeply involved in the control of neuronal activity and the synaptic plasticity by serving as a protein kinase that phosphorylates various proteins and thereby modifies the functions of the proteins.
Furthermore, CaMKII is considered to play an important role in higher brain functions including learning and memory, inhibition of epileptic seizure, and inhibition of brain disorder that may be caused by cerebral ischemia (see "PROTEIN, NUCLEIC ACID, AND ENZYME", Vol. 47, No. 1: 51-57, 2002).
CaMKII present in the central nervous system has a multimeric structure whose component is an alpha subunit (CaMKIIalpha ) and a beta subunit (CaMKIIbeta ).
These subunits are highly homologous to each other.
Each subunit has the protein kinase activity, the Ca2+/calmodulin-binding ability, and the capacity of association between subunits.
The alpha subunit is expressed abundantly in the forebrain, while the beta subunit is expressed abundantly in the cerebellum.
It is therefore considered that the alpha subunit is mainly responsible for the above-mentioned CaMKII function.
Until now, simple knockout mice that have lost CaMKIIalpha protein itself have been produced.
Behavior disorders having a relationship with memory and learning, and electrophysiological disorders have been found in these mice.
Furthermore, the findings of vulnerability to both convulsion and cerebral ischemia have been also reported (see Science, Vol. 257: 201-206 and 206-211, 1992; Proc.
Natl. Acad. Sci. USA, Vol. 92: 6852-6855, 1995; and J. Cereb. Blood Flow Metab., Vol. 16: 1-6, 1996).
However, simple knockout mice have lost all of the following three functions: (1) a function as a protein kinase that phosphorylates proteins; (2) a function of binding to calmodulin that is a Ca2+-binding protein; and (3) a function of working as a structural protein through binding between CaMKII subunits or binding to other proteins.
Thus, it was unclear which loss of function among these functions (1) to (3) was responsible for the various disorders found in the knockout mice.
On the other hand, experiments using cultured neurons and brain slices suggest that the function (1) as a protein kinase is more important.
Hence, in order to elucidate the pathology of neuropsychiatric diseases and the molecular mechanisms of brain functions, it is necessary to produce and analyze a specific loss-of-functional animal in which the function (1) alone is specifically lost (so as to say, a "functionally knockout animal"), to distinguishably study the aforementioned functions (1) to (3) of CaMKII.

特許請求の範囲(英語) [claim1]
1. An inactive Ca2+/calmodulin-dependent protein kinase IIalpha (CaMKIIalpha ) knockin nonhuman animal, wherein a CaMKIIalpha gene of one or both of homologous chromosomes is substituted into an inactive type so that an inactive CaMKIIalpha is expressed, wherein lysine corresponding to Lys-42 in the catalytic domain of mouse CaMKIIalpha is substituted by arginine; and thereby a protein kinase activity of CaMKIIalpha is specifically impaired while a calmodulin binding capacity of CaMKIIalpha and a capacity of multimerizing subunits are maintained, wherein the nucleus accumbens of the brain of the inactive CaMKIIalpha knockin nonhuman animal has lower neuronal activity as compared to that of a wild-type, while there is no substantial difference in neuronal activities in the cerebral cortex and caudate-putamen as compared to those of the wild-type,
and wherein the inactive CaMKIIalpha knockin nonhuman animal is produced by a gene targeting method.
[claim2]
2. The inactive CaMKIIalpha knockin nonhuman animal of claim 1, wherein the inactive CaMKIIalpha knockin nonhuman animal is a rodent animal.
[claim3]
3. The inactive CaMKIIalpha knockin nonhuman animal of claim 2, wherein the inactive CaMKIIalpha knockin nonhuman animal is a mouse.
  • 発明者/出願人(英語)
  • YAMAGATA YOKO
  • YANAGAWA YUCHIO
  • JAPAN SCIENCE AND TECHNOLOGY AGENCY
国際特許分類(IPC)
米国特許分類/主・副
  • 2016/01/01
参考情報 (研究プロジェクト等) CREST Understanding the Brain AREA
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