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Modeling Regulation of Cardiac K_ATP and L-type Ca²⁺ Currents by ATP, ADP, and Mg²⁺

Department of Bioengineering, University of California San Diego, La Jolla, California

Correspondence: Address reprint requests to Dr. Anushka Michailova, Dept. of Bioengineering, University of California San Diego, La Jolla, CA 92093-0412. E-mail: amihaylo{at}bioeng.ucsd.edu.

Changes in cytosolic free Mg²⁺ and adenosine nucleotide phosphates affect cardiac excitability and contractility. To investigate how modulation by Mg²⁺, ATP, and ADP of K_ATP and L-type Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ current during rapid increase in MgATP, and 4), demonstrates that decreased ATP/ADP ratio with normal total Mg²⁺ or increased free Mg²⁺ with normal ATP and ADP activate K_ATP current, shorten action potential, and alter ionic currents and intracellular Ca²⁺ signals. The model predictions are in agreement with experimental data measured under normal and a variety of pathological conditions.