title: Modeling K,ATP--dependent excitability in pancreatic islets.
abstract: In pancreatic ?-cells, K,ATP channels respond to changes in glucose to regulate cell excitability and insulin release. Confirming a high sensitivity of electrical activity to K,ATP activity, mutations that cause gain of K,ATP function cause neonatal diabetes. Our aim was to quantitatively assess the contribution of K,ATP current to the regulation of glucose-dependent bursting by reproducing experimentally observed changes in excitability when K,ATP conductance is altered by genetic manipulation. A recent detailed computational model of single cell pancreatic ?-cell excitability reproduces the ?-cell response to varying glucose concentrations. However, initial simulations showed that the model underrepresents the significance of K,ATP activity and was unable to reproduce K,ATP conductance-dependent changes in excitability. By altering the ATP and glucose dependence of the L-type Ca(2+) channel and the Na-K ATPase to better fit experiment, appropriate dependence of excitability on K,ATP conductance was reproduced. Because experiments were conducted in islets, which contain cell-to-cell variability, we extended the model from a single cell to a three-dimensional model (10×10×10 cell) islet with 1000 cells. For each cell, the conductance of the major currents was allowed to vary as was the gap junction conductance between cells. This showed that single cell glucose-dependent behavior was then highly variable, but was uniform in coupled islets. The study highlights the importance of parameterization of detailed models of ?-cell excitability and suggests future experiments that will lead to improved characterization of ?-cell excitability and the control of insulin secretion.
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri; Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, Missouri; Department of Center for Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Silva
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri; Department of Center for Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Paige
authors.initials: P
authors.lastname: Cooper
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri; Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, Missouri; Department of Center for Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, Missouri. Electronic address: cnichols@wustl.edu.
authors.forename: Colin G
authors.initials: CG
authors.lastname: Nichols
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism; D003198:Computer Simulation; D004553:Electric Conductivity; D017629:Gap Junctions / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D007515:Islets of Langerhans / Q000502:physiology*; D054086:KATP Channels / Q000378:metabolism*; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008954:Models, Biological; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D012984:Software; D000099161:Kcnj11 Channel
chemical_list: D000255:Adenosine Triphosphate; D020746:Calcium Channels, L-Type; D005947:Glucose; D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; D000254:Sodium-Potassium-Exchanging ATPase; D000099161:Kcnj11 Channel