G PROTEIN-DEPENDENT SIGNAL : DESENSITIZATION AND DISEASES
Grant-in-Aid for Scientific Research (C)
|Allocation Type||Single-year Grants |
|Research Institution||The University of Tokyo |
MAKITA Noriko The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手 (60353455)
IIRI Taroh The University of Tokyo, Faculty of Medicine, Project Lecturer, 医学部附属病院, 特任講師 (90313022)
|Project Period (FY)
2005 – 2006
Completed(Fiscal Year 2006)
|Budget Amount *help
¥2,700,000 (Direct Cost : ¥2,700,000)
Fiscal Year 2006 : ¥1,200,000 (Direct Cost : ¥1,200,000)
Fiscal Year 2005 : ¥1,500,000 (Direct Cost : ¥1,500,000)
|Keywords||G protein / GPCR / molecular mechanism / desensitization / disease / G protein disease / レセプター|
1) ELUCIDATION OF DESENSITIZATION OF G PROTEINS BASED ON THE ANALYSIS OF G PROTEIN DISEASES
(1) G protein-coupled receptor (GPCR) signaling and desensitization
Desensitization 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 proteins
We 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 desensitization
We have analyzed the effect of transfection of GRK, arrestin, and Gt on GPCR dependent signal and desentization.
(2) Signal Switching
We 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
Research Products (20results)