Model Study of ATP and ADP Buffering, Transport of Ca2+ and Mg2+,and Regulation of Ion Pumps in Ventricular Myocyte

Abstract

We extended the model of the ventricular myocyte by Winslow et al. (Circ. Res 1999, 84:571-586) by incorporating equations for Ca(2+) and Mg(2+) buffering and transport by ATP and ADP and equations for MgATP regulation of ion transporters (Na(+)-K(+) pump, sarcolemmal and sarcoplasmic Ca(2+) pumps). The results indicate that, under normal conditions, Ca(2+) binding by low-affinity ATP and diffusion of CaATP may affect the amplitude and time course of intracellular Ca(2+) signals. The model also suggests that a fall in ATP/ADP ratio significantly reduces sarcoplasmic Ca(2+) content, increases diastolic Ca(2+), lowers systolic Ca(2+), increases Ca(2+) influx through L-type channels, and decreases the efficiency of the Na(+)/Ca(2+) exchanger in extruding Ca(2+) during periodic voltage-clamp stimulation. The analysis suggests that the most important reason for these changes during metabolic inhibition is the down-regulation of the sarcoplasmic Ca(2+)-ATPase pump by reduced diastolic MgATP levels. High Ca(2+) concentrations developed near the membrane might have a greater influence on Mg(2+), ATP, and ADP concentrations than that of the lower Ca(2+) concentrations in the bulk myoplasm. The model predictions are in general agreement with experimental observations measured under normal and pathological conditions.

Dictyosteliummyosin-IE is a fast molecular motor involved in phagocytosis

“…Our results show that ADP-release from acto·myosin-IE is affected by changes in the concentration of free Mg 2+ that are within the physiological range. The apparent K i of~800 M for free Mg 2+ makes the coordination of the Mg 2+ ion at the nucleotide-binding site responsive to changes that lie well within the range of physiological free-Mg 2+ concentrations in D. discoideum and many other cell types (Michailova and McCulloch, 2001;Satre and Martin, 1985). The resulting threefold modulation of myosin-IE motor velocity at zero load conditions is small but the concomitant increase in the ability of the protein to generate tension needs to be considered as well.…”

Excitation-contraction coupling and mitochondrial energetics

“…Computational modeling predicted a temporarily and spatially limited increase of the Ca 2+ -concentration ([Ca 2+ ]) in the range from ∼10 µM to ∼7 mM within the first couple of ms after opening of the RyR2 [14,15,102,133,151,152,158,174,217]. This high junctional [Ca 2+ ] decays rapidly by diffusion into the submembrane space and then further into the bulk cytosol, where it peaks later and at much lower concentrations than in the cleft (at ∼1.5 µM in the submembrane space and ∼0.5 µM in the bulk cytosol [174,209]).…”

“…The Ca 2+ influx triggers the opening of the ryanodine receptor (RyR2 subtype), inducing the release of even greater amounts of Ca 2+ from the sarcoplasmic reticulum (SR), a process termed Ca 2+ -induced Ca 2+ -release (CICR) [14,15,63,64]. The Ca 2+ released from RyRs floods the space between the SR and the cell membrane (i. e., the dyadic or junctional cleft), a gap of typically ∼10 nm and covering a volume with a radius of ∼200 nm [102,151].Computational modeling predicted a temporarily and spatially limited increase of the Ca 2+ -concentration ([Ca 2+ ]) in the range from ∼10 µM to ∼7 mM within the first couple of ms after opening of the RyR2 [14,15,102,133,151,152,158,174,217]. This high junctional [Ca 2+ ] decays rapidly by diffusion into the submembrane space and then further into the bulk cytosol, where it peaks later and at much lower concentrations than in the cleft (at ∼1.5 µM in the submembrane space and ∼0.5 µM in the bulk cytosol [174,209]).…”

Strategies and Tactics in Multiscale Modeling of Cell-to-Organ Systems

“…A cardiac cellular action potential model requires accounting for many ionic currents, ionic buffering, and ion pumps and exchangers for maintenance of the intracellular milieu, about 120 equations in the model of Michailova and McCulloch [3]. Even so, a pair of equations from Fitzhugh [4] and Nagumo [5] can represent the propagation of excitation through the myocardium very well, a huge reduction in computation time.…”

“…The assurance of correctness of the code starts with writing the equations to provide internal checks for unitary balance, providing units for all parameters and variables and using a compiler or code checker that checks every equation, as is done in the JSim simulation system. 3 We strongly advocate incorporating unit balance checking in every simulation system. The second step is to write into the particular program the equations checking for balances of mass, charge, momentum, energy, etc.…”