G PROTEIN-DEPENDENT SIGNAL : DESENSITIZATION AND DISEASES

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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