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G PROTEIN-DEPENDENT SIGNAL : DESENSITIZATION AND DISEASES

G 蛋白依赖性信号：脱敏和疾病

基本信息

批准号：
17590955
负责人：
MAKITA Noriko
金额：
$ 1.73万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590955/
关键词：
G protein GPCR molecular mechanism desensitization disease G protein disease レセプター

项目摘要

1) ELUCIDATION OF DESENSITIZATION OF G PROTEINS BASED ON THE ANALYSIS OF G PROTEIN DISEASES(1) G protein-coupled receptor (GPCR) signaling and desensitizationDesensitization may explain, at least in part, each cell specific responsiveness to receptor-dependent signaling. We analyzed the potential role of lipid modification on G proteins in signal desensitization.(2) Potential desensitization mechanism on G proteinsWe have shown that overexpression of palmitoyl esterase causes signal inhibition and translocation of Gs.2) NOVEL MECHANISMS OF RECEPTOR-G PROTEIN SIGNAL AND PATHOPHYSIOLOGY(1) Gene delivery of molecules working on GPCR desensitizationWe have analyzed the effect of transfection of GRK, arrestin, and Gt on GPCR dependent signal and desentization.(2) Signal SwitchingWe have discovered a novel Ca-sensing receptor (CaSR) autoantibody in a human disease, acquired hypocalciuric hypercalcemia. CaSR is known to activate multiple G proteins including Gq and Gi, thereby activates a variety of signals and inhibits parathyroid hormone secretion. We have shown our autoantibody works as an allosteric modulator to CaSR and that a Ca-stimulated CaSR primed by this autoatibody adopts a unique conformation that activates Gq but not Gi. We speculate that physiological modulators may exist that enable an agonist to specifically activate only one signaling pathway via a GPCR that activates multiple signaling pathways.(3) Analysis and Screening of inverse agonists to GPCRs

1)（1）G蛋白偶联受体（GPCR）信号转导与脱敏脱敏作用脱敏作用至少可以部分解释细胞对受体依赖性信号转导的特异性反应。我们分析了G蛋白的脂质修饰在信号脱敏中的潜在作用。(2)2）受体-G蛋白信号转导和病理生理的新机制（1）GPCR脱敏分子的基因转导我们分析了GRK、arrestin和Gt转染对GPCR依赖性信号转导和脱敏的影响。(2)我们在人类获得性低钙尿症高钙血症中发现了一种新的钙敏感受体（CaSR）自身抗体。已知CaSR激活多种G蛋白，包括Gq和Gi，从而激活多种信号并抑制甲状旁腺激素分泌。我们已经表明我们的自身抗体作为CaSR的变构调节剂起作用，并且由该自身抗体引发的Ca刺激的CaSR采用激活Gq但不激活Gi的独特构象。我们推测，可能存在生理调节剂，使激动剂通过GPCR激活多个信号通路，特异性地激活只有一个信号通路。(3)GPCR反向激动剂的分析与筛选