Theoretical Investigations into the Quantitative Mechanisms Underlying the Regulation of [cAMP]<sub>i</sub>, Membrane Excitability and [Ca<sup>2+</sup>]<sub>i</sub> during GLP-1 Stimulation in Pancreatic β Cells
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- Takeda Yukari
- Department of Bioinformatics, College of Life Sciences, Ritsumeikan University
Bibliographic Information
- Other Title
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- 膵β細胞におけるGLP-1受容体刺激による細胞内cAMP濃度調節並びに膜興奮性及びカルシウム濃度制御機構のシミュレーション研究
- Symposium Review 膵β細胞におけるGLP-1受容体刺激による細胞内cAMP濃度調節並びに膜興奮性及びカルシウム濃度制御機構のシミュレーション研究
- Symposium Review スイvサイボウ ニ オケル GLP-1 ジュヨウタイ シゲキ ニ ヨル サイボウ ナイ cAMP ノウド チョウセツ ナラビニ マク コウフンセイ オヨビ カルシウム ノウド セイギョ キコウ ノ シミュレーション ケンキュウ
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Abstract
Upon elevation of plasma glucose concentration, pancreatic β-cells generate bursts of action potentials to induce cyclic changes in [Ca2+]i regulating insulin release. Glucose-dependent insulin secretion is synergistically enhanced by glucagon-like peptide-1 (GLP-1), which increases [cAMP]i and activates protein kinase A (PKA) and exchange protein activated by cAMP (Epac). The insulinotropic effect of GLP-1 is mediated, at least in part, by modulating multiple ion channels/transporters at the plasma membrane and ER through PKA- and EPAC-dependent mechanisms, which increase membrane excitability and intracellular Ca2+ release. However, because of complex interactions between multiple cellular factors involved in the GLP-1 effects, quantitative aspects of the molecular/ionic mechanisms have not yet been determined. We thus performed simulation studies and mathematical analysis to investigate how GLP-1 signals control [cAMP]i and subsequently modify the bursting activities and Ca2+ dynamics. First, a GLP-1 receptor signal transduction model was developed and introduced to our β-cells model. Secondly, modulatory effects of PKA/Epac on ion channels/transporters were incorporated based on experimental studies. Increases in the frequency and duration of the bursting activity observed during GLP-1 stimulation were well reconstructed by our model, and lead potential analysis quantitatively determined the functional role of each ion channel/transporter in modifying the burst pattern. Finally, an IP3R model was developed to reproduce GLP-1-induced Ca2+ transients/oscillations. Instantaneous equilibrium analysis and bifurcation analysis also elucidated the quantitative mechanisms involved in generating IP3R-mediated Ca2+ mobilization. The results of this theoretical analysis of the effects of GLP-1 on membrane excitability/Ca2+ dynamics are discussed in this review.<br>
Journal
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- YAKUGAKU ZASSHI
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YAKUGAKU ZASSHI 136 (3), 467-471, 2016-03-01
The Pharmaceutical Society of Japan
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Details 詳細情報について
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- CRID
- 1390282681103264000
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- NII Article ID
- 130005131244
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- NII Book ID
- AN00284903
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- ISSN
- 13475231
- 00316903
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- NDL BIB ID
- 027152461
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- PubMed
- 26935088
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- Text Lang
- ja
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- Data Source
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- JaLC
- NDL
- Crossref
- PubMed
- CiNii Articles
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- Abstract License Flag
- Disallowed