G PROTEIN-DEPENDENT SIGNAL : DESENSITIZATION AND DISEASES

(1) G蛋白偶联受体（GPCR）信号转导与脱敏脱敏至少在一定程度上可以解释每个细胞对受体依赖性信号转导的特异性反应。我们分析了脂质修饰对G蛋白在信号脱敏中的潜在作用。(2) G蛋白脱敏的潜在机制研究表明，棕榈酰酯酶的过表达可导致G蛋白的信号抑制和易位。(2)受体-G蛋白信号和病理生理学的新机制(1)GPCR脱敏分子的基因传递我们分析了转染GRK、抑制素和Gt对GPCR依赖信号和脱敏的影响。(2)信号转换我们在人类获得性低钙高钙血症中发现了一种新的钙感应受体（CaSR）自身抗体。已知CaSR可激活Gq、Gi等多种G蛋白，从而激活多种信号，抑制甲状旁腺激素分泌。我们已经证明，我们的自身抗体可以作为CaSR的变构调节剂，并且由这种自身抗体引发的ca刺激的CaSR采用一种独特的构象，可以激活Gq而不是Gi。我们推测可能存在生理调节剂，使激动剂通过激活多种信号通路的GPCR特异性激活仅一条信号通路。(3) gpcr反受体激动剂的分析与筛选

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