Modeling regulation of cardiac KATP and L-type Ca2+ currents by ATP, ADP, and Mg2+

Modeling regulation of cardiac KATP and L-type Ca2+ currents by ATP, ADP, and Mg2+

Model Status

This CellML model runs in both COR and PCEnv. The units have been checked and they are consistent. Unfortunately the CellML model is still not quite reproducing the published results. We will continue to curate the model and hope to get it fully working.

Model Structure

ABSTRACT: 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.

Schematic representation of Kir6.2 and SUR2A subunit stoichiometry in cardiac octameric KATP channel. It is assumed that the single ATP molecule is sufficient to close the channel and that the binding of 2MgADP molecules to one SUR2A subunit increases the channel open probability.
Schematic diagram of the full cell model illustrating Ca2+ and Mg2+ buffering and transport by ATP and ADP, adenine nucleotides regulation of ionic channels and pumps, and electrophysiology in a ventricular myocyte.

The original paper reference is cited below:

Modeling Regulation of Cardiac KATP and L-type Ca2+ Currents by ATP, ADP, and Mg2+, Anushka Michailova, Jeffrey Saucerman, Mary Ellen Belik, and Andrew D. McCulloch, 2005, Biophysical Journal. PubMed ID: 18339738