Modeling regulation of cardiac KATP and L-type Ca2+ currents by ATP, ADP, and Mg2+.
Changes in cytosolic free Mg(2+) and adenosine nucleotide phosphates affect cardiac excitability and contractility. To investigate how modulation by Mg(2+), ATP, and ADP of K(ATP) and L-type Ca(2+) channels influences excitation-contraction coupling, we incorporated equations for intracellular ATP and MgADP regulation of the K(ATP) current and MgATP regulation of the L-type Ca(2+) current in an ionic-metabolic model of the canine ventricular myocyte. The new model: 1), quantitatively reproduces a dose-response relationship for the effects of changes in ATP on K(ATP) current, 2), simulates effects of ADP in modulating ATP sensitivity of K(ATP) channel, 3), predicts activation of Ca(2+) current during rapid increase in MgATP, and 4), demonstrates that decreased ATP/ADP ratio with normal total Mg(2+) or increased free Mg(2+) with normal ATP and ADP activate K(ATP) current, shorten action potential, and alter ionic currents and intracellular Ca(2+) signals. The model predictions are in agreement with experimental data measured under normal and a variety of pathological conditions.
Michailova
Anushka
A
Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA. amihaylo@bioeng.ucsd.edu
Saucerman
Jeffrey
J
Belik
Mary Ellen
ME
McCulloch
Andrew D
AD
D000244:Adenosine Diphosphate / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology*; D002478:Cells, Cultured; D003198:Computer Simulation; D006706:Homeostasis / Q000502:physiology; D015640:Ion Channel Gating / Q000502:physiology; D008274:Magnesium / Q000378:metabolism*; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000502:physiology; D032383:Myocytes, Cardiac / Q000502:physiology*; D015221:Potassium Channels / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D020746:Calcium Channels, L-Type; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D008274:Magnesium
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