A model of action potentials and fast Ca2+ dynamics in pancreatic beta-cells.
We examined the ionic mechanisms mediating depolarization-induced spike activity in pancreatic beta-cells. We formulated a Hodgkin-Huxley-type ionic model for the action potential (AP) in these cells based on voltage- and current-clamp results together with measurements of Ca(2+) dynamics in wild-type and Kv2.1 null mouse islets. The model contains an L-type Ca(2+) current, a "rapid" delayed-rectifier K(+) current, a small slowly-activated K(+) current, a Ca(2+)-activated K(+) current, an ATP-sensitive K(+) current, a plasma membrane calcium-pump current and a Na(+) background current. This model, coupled with an equation describing intracellular Ca(2+) homeostasis, replicates beta-cell AP and Ca(2+) changes during one glucose-induced spontaneous spike, the effects of blocking K(+) currents with different inhibitors, and specific complex spike in mouse islets lacking Kv2.1 channels. The currents with voltage-independent gating variables can also be responsible for burst behavior. Original features of this model include new equations for L-type Ca(2+) current, assessment of the role of rapid delayed-rectifier K(+) current, and Ca(2+)-activated K(+) currents, demonstrating the important roles of the Ca(2+)-pump and background currents in the APs and bursts. This model provides acceptable fits to voltage-clamp, AP, and Ca(2+) concentration data based on in silico analysis.
Fridlyand
L E
LE
Department of Medicine, University of Chicago, Chicago, Illinois, USA.
Jacobson
D A
DA
Kuznetsov
A
A
Philipson
L H
LH
D000200:Action Potentials; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling; D002462:Cell Membrane / Q000502:physiology; D003198:Computer Simulation; D051668:Delayed Rectifier Potassium Channels / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008959:Models, Neurological; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors; D051669:Shab Potassium Channels / Q000235:genetics; D012964:Sodium / Q000378:metabolism; D019789:Tetraethylammonium / Q000494:pharmacology; D013995:Time
D020746:Calcium Channels, L-Type; D051668:Delayed Rectifier Potassium Channels; C496990:Kcnb1 protein, mouse; D024642:Potassium Channels, Voltage-Gated; D051669:Shab Potassium Channels; D019789:Tetraethylammonium; D000255:Adenosine Triphosphate; D012964:Sodium; D005947:Glucose; D011188:Potassium; D002118:Calcium