Identification of factors that modify either the heterodimerization of G protein-coupled receptors or the trafficking of heterodimerized receptors to the cell surface
鉴定改变 G 蛋白偶联受体异二聚化或异二聚化受体运输至细胞表面的因素
基本信息
- 批准号:15500262
- 负责人:
- 金额:$ 2.43万
- 依托单位:
- 依托单位国家:日本
- 项目类别:Grant-in-Aid for Scientific Research (C)
- 财政年份:2003
- 资助国家:日本
- 起止时间:2003 至 2004
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
GABA is known to act as an inhibitory neurotransmitter on the central and peripheral nervous system. One of GABA receptors, the metabotropic GABAB receptor has been cloned in 1998. Functional GABA_B receptors are required to be formed with two GABAB receptor subunits, GABAB1 and GABAB2. Recent progress has also shown that not GABAB receptors but also many types of GPCRs such as μ- and δ-opioid receptors form heterodimer. Further, properties of such heterodimeric receptors have been reported to be differed from their parental monomeric receptors. However, nothing is known how heterodimers are formed and none of the compounds have been identified that modify the heterodimerization of GPCRs.In the present study we focused on identification of factors that modify either formation of the heterodimerized GPCRs or trafficking of heterodimerized GPCR to the cell surface.Our results showed that heterodimerization of GPCRs already occurred in the Golgi or endoplasmic reticulum and then heterodimer formed there were trafficked to cell surface. In addition we demonstrated that geldanamycin, an inhibitor of HSP90, which acts as chaperone in the cells, inhibited the trafficking of the heterodimerized receptors to the cells as well as formation of heterodimerization. These results indicated that some protein chaperone such as HSP 90 could be involved in the formation, and trafficking of the heterodimerized receptors to the cell surface.We are now searching for compounds that modify formation and trafficking of the heterodimerized receptors. Such compounds will shed lights to open new category of drugs for modification of GPCR dimerization.
众所周知,GABA是中枢和外周神经系统的抑制性神经递质。代谢型GABAB受体是GABA受体之一,于1998年被克隆。功能性的GABA_B受体需要由两个GABAB受体亚基GABAB1和GABAB2组成。最近的进展也表明,不仅是GAAB受体,而且许多类型的GPCRs,如μ-和δ-阿片受体也形成异源二聚体。此外,据报道,这种异二聚体受体的性质不同于它们的亲本单体受体。然而,目前还不知道异二聚体是如何形成的,也没有发现任何化合物可以改变GPCRs的异二聚化。在本研究中,我们主要研究了影响异二聚化GPCRs形成或运输到细胞表面的因素。我们的结果表明,GPCRs的异二聚化已经发生在高尔基体或内质网中,然后在那里形成的异二聚体被运输到细胞表面。此外,我们还证明了热休克蛋白90的抑制剂格尔达那霉素能抑制异二聚化受体向细胞的转运和异二聚化的形成。这些结果表明,一些蛋白伴侣,如HSP90,可能参与了异二聚化受体的形成和运输到细胞表面。我们正在寻找能够改变异二聚化受体的形成和运输的化合物。这些化合物将为修饰GPCR二聚体开辟新的药物类别。
项目成果
期刊论文数量(85)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
KAWAKAMI, S., UEZONO, Y., MIKIMOTO, N., ENJOJI, A., et al.: "Characterizarion of GABAB receptors involved in inhibition of motility associated with acetylcholine release in the dog small intestine"Journal of Pharmacological Sciences. (In Press). (2004)
KAWAKAMI, S.、UEZONO, Y.、MIKIMOTO, N.、ENJOJI, A.等人:“参与抑制狗小肠乙酰胆碱释放相关运动的 GABAB 受体的特征”药理学科学杂志。
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Selective blockade of nicotinic acetylcholine reseptors by pimobendan, a drug for the treatment of heart failure : reduction of catecholamine secretion and synthesis in adrenal medullary cells.
匹莫苯丹(一种治疗心力衰竭的药物)选择性阻断烟碱乙酰胆碱受体:减少肾上腺髓质细胞中儿茶酚胺的分泌和合成。
- DOI:
- 发表时间:2005
- 期刊:
- 影响因子:0
- 作者:TOYOHIRA;Y.;KUBO;T.;UEZONO;Y.et al.
- 通讯作者:Y.et al.
The effect of the tramadol metabolite O-demethyl tramadol, on the muscarinic receptor-induced responses in Xenopus oocytes expressing the cloned M1 or M3 receptors.
曲马多代谢物 O-去甲基曲马多对表达克隆 M1 或 M3 受体的爪蟾卵母细胞中毒蕈碱受体诱导的反应的影响。
- DOI:
- 发表时间:2005
- 期刊:
- 影响因子:0
- 作者:NAKAMURA;M.;MINAMI;K.;UEZONO;Y.;et al.
- 通讯作者:et al.
A forskolin derivative, colforsin daropate hydrochloride, inhibits the decrease in cortical renal blood flow induced by noradrenaline or angiotensin II in anesthetized nats.
毛喉素衍生物 Colforsin daropate 盐酸盐可抑制麻醉状态下由去甲肾上腺素或血管紧张素 II 引起的皮质肾血流减少。
- DOI:
- 发表时间:2004
- 期刊:
- 影响因子:0
- 作者:OGATA;J.;MINAMI;K.;UEZONO;Y.et al.
- 通讯作者:Y.et al.
Mechanism of cytosolic Ca^<2+> suppression by prostaglandin E_2 receptors in rat melanotrophs.
大鼠黑素细胞中前列腺素E_2受体抑制细胞质Ca^2的机制。
- DOI:
- 发表时间:2003
- 期刊:
- 影响因子:0
- 作者:NAGATA T;HARAYAMA N;SAKAKI N;INOUE M;TANAKA K;TOYOHIRA Y;UEZONO;Y et al.
- 通讯作者:Y et al.
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UEZONO Yasuhito其他文献
Lipid metabolism in cancer cachexia and caloric restriction inadipose tissue, effects of Rikkunshito
癌症恶病质中的脂质代谢和脂肪组织中的热量限制,六君子汤的作用
- DOI:
- 发表时间:
2014 - 期刊:
- 影响因子:0
- 作者:
MIYAKAWA Ryota;SUDO Yuka;OTUKA Hiroki;GOTO Akihumi;KASHIWASE Yohei;UEZONO Yasuhito;HIGAMI Yoshikazu. - 通讯作者:
HIGAMI Yoshikazu.
UEZONO Yasuhito的其他文献
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{{ truncateString('UEZONO Yasuhito', 18)}}的其他基金
Management of intolerable pain: development of novel methods for the persistent analgesia by simultaneous activation of heterodimerized Gi-coupled receptors
难以忍受的疼痛的管理:通过同时激活异二聚化 Gi 偶联受体来开发持续镇痛的新方法
- 批准号:
24590740 - 财政年份:2012
- 资助金额:
$ 2.43万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Overcoming refractory pain : prevention of tolerance of pain by simultaneous activation of G_<i/o>-coupled receptors
克服难治性疼痛:通过同时激活 G_<i/o> 偶联受体来预防疼痛耐受
- 批准号:
21600009 - 财政年份:2009
- 资助金额:
$ 2.43万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Overcome of intolerable pain : improvement of intrathecal drugapplication and its clinical use.
克服难以忍受的疼痛:鞘内用药的改进及其临床应用。
- 批准号:
19500325 - 财政年份:2007
- 资助金额:
$ 2.43万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Attempt of obstinacy pain easing by spinal cord GABA-B receptor continuation activation.
尝试通过脊髓 GABA-B 受体持续激活来缓解顽固性疼痛。
- 批准号:
17500254 - 财政年份:2005
- 资助金额:
$ 2.43万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Analysis of the molecular mechanisms of formation and trafficking to the cell surface of the G protein-coupled receptors that require accessory proteins for their expression.
分析需要辅助蛋白表达的 G 蛋白偶联受体形成和运输到细胞表面的分子机制。
- 批准号:
13680846 - 财政年份:2001
- 资助金额:
$ 2.43万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Identification and analysis of factors that regulate cell surface expression of G-protein coupled receptor
G蛋白偶联受体细胞表面表达调节因子的鉴定与分析
- 批准号:
11680770 - 财政年份:1999
- 资助金额:
$ 2.43万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
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A Novel high resolution MS platform for high-throughput screening of G protein-coupled receptors
用于高通量筛选 G 蛋白偶联受体的新型高分辨率 MS 平台
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