HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 293/6/C1924    most recent 00555.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Fridlyand, L. E. Articles by Philipson, L. H. Search for Related Content PubMed PubMed Citation Articles by Fridlyand, L. E. Articles by Philipson, L. H.

RECEPTORS AND SIGNAL TRANSDUCTION

Regulation of cAMP dynamics by Ca²⁺ and G protein-coupled receptors in the pancreatic β-cell: a computational approach

Department of Medicine, University of Chicago, Chicago, Illinois

Submitted 31 October 2006 ; accepted in final form 1 October 2007

In this report we describe a mathematical model for the regulation of cAMP dynamics in pancreatic β-cells. Incretin hormones such as glucagon-like peptide 1 (GLP-1) increase cAMP and augment insulin secretion in pancreatic β-cells. Imaging experiments performed in MIN6 insulinoma cells expressing a genetically encoded cAMP biosensor and loaded with fura-2, a calcium indicator, showed that cAMP oscillations are differentially regulated by periodic changes in membrane potential and GLP-1. We modeled the interplay of intracellular calcium (Ca²⁺) and its interaction with calmodulin, G protein-coupled receptor activation, adenylyl cyclases (AC), and phosphodiesterases (PDE). Simulations with the model demonstrate that cAMP oscillations are coupled to cytoplasmic Ca²⁺ oscillations in the β-cell. Slow Ca²⁺ oscillations (<1 min^–1) produce low-frequency cAMP oscillations, and faster Ca²⁺ oscillations (>3–4 min^–1) entrain high-frequency, low-amplitude cAMP oscillations. The model predicts that GLP-1 receptor agonists induce cAMP oscillations in phase with cytoplasmic Ca²⁺ oscillations. In contrast, observed antiphasic Ca²⁺ and cAMP oscillations can be simulated following combined glucose and tetraethylammonium-induced changes in membrane potential. The model provides additional evidence for a pivotal role for Ca²⁺-dependent AC and PDE activation in coupling of Ca²⁺ and cAMP signals. Our results reveal important differences in the effects of glucose/TEA and GLP-1 on cAMP dynamics in MIN6 β-cells.

adenylyl cyclase; calcium ion; glucagon-like peptide 1; modeling; oscillations

This article has been cited by other articles:

				M. G. Pedersen, A. Corradin, G. M Toffolo, and C. Cobelli A subcellular model of glucose-stimulated pancreatic insulin secretion Phil Trans R Soc A, October 13, 2008; 366(1880): 3525 - 3543. [Abstract] [Full Text] [PDF]