2011 Fiscal Year Final Research Report
GLP-1 Receptor Signaling in Pancreaticβ-cells
| Project/Area Number |
22890086
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| Research Category |
Grant-in-Aid for Research Activity Start-up
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| Allocation Type | Single-year Grants |
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| Research Field |
General physiology
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| Research Institution | Kyoto University |
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Principal Investigator |
TAKEDA Yukari 京都大学, 医学研究科, 助教 (20582159)
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| Project Period (FY) |
2010 – 2011
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| Keywords | 生理学 / 細胞・組織 / シグナル伝達 |
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| Research Abstract |
Glucagon-like peptide-1(GLP-1) elevates intracellular concentration of cAMP([cAMP]) and facilitates glucose-dependent insulin secretion in pancreaticβ-cells. However, because of complex interactions between signaling factors and effectors, the detailed mechanism underlying elevated insulin secretion has not been elucidated. We thus utilized 'bioinformatics' to quantitatively analyze the GLP-1 effects. First, we reconstructed a minimal mathematical model of GLP-1 receptor signal transduction, which involves GLP-1 receptor, Gs protein, adenylate cyclase(AC), phosphodiesterase(PDE). By fitting this theoretical reaction scheme to key experimental records of the GLP-1 response, the parameters determining individual reaction steps were estimated. The model reconstructed satisfactorily the dynamic changes in cAMP, and predicted the activities of cAMP effectors, protein kinase A(PKA) and cAMP-regulated guanine nucleotide exchange factor(cAMP-GEF or Epac) during GLP-1 stimulation. The simulations also predicted the presence of two sequential desensitization steps of the GLP1 receptor that occur with fast and very slow reaction rates. The cross talk between glucose-and GLP-1-dependent signal cascades for cAMP synthesis was well reconstructed by integrating the direct regulation of AC and PDE by [Ca^<2+>]. We finally incorporated the GLP-1 signaling cascade model into the β-cell model. By cording the PKA and Epac induced modulation on ion channels(L-type Ca^<2+> currents, Voltage-dependent K+channels, ATP-dependent K+channels), the GLP-1 effects on the magnitude as well as the amplitude of bursts of action potentials were well reconstructed. We will be able to quantitatively analyze the effects of GLP-1 on each signaling effectors on membrane excitability and Ca^<2+> signaling when models of Ca^<2+> releasing channels on endoplasmic reticulum(ER) are completed.
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