Modeling the mechanism of metabolic oscillations in ischemic cardiac myocytes.

Oscillations in energy metabolism have been observed in a variety of cells under metabolically deprived conditions such as ischemia. In cardiac ventricular myocytes these metabolic oscillations may cause oscillations in the action potential duration, creating the potential for cardiac arrhythmias during ischemia (O'Rourke, 2000). A mathematical model of the mechanism behind metabolic oscillations is developed here. The model consists of descriptions of the mitochondrial components that regulate mitochondrial membrane potential (Psi), mitochondrial inorganic phosphate concentration, mitochondrial magnesium concentration, and cellular NADH and NAD(+) concentrations. Using parameters from the experimental literature, the model produces physiological values for these both under normoxic (steady state) and ischemic (oscillatory) conditions. The model includes the mitochondrial inner membrane anion channel (IMAC), the centum picosiemen channel (mCS), the phosphate carrier (PIC), and the respiration driven proton pumps. The model suggests that these are the essential components for producing oscillations with mCS essential for the rapid depolarization, PIC for the recovery from depolarization, and IMAC for the slow depolarization between depolarization peaks. A decrease of the inner membrane potential due to ischemia or experimental conditions seems to be a triggering factor for the oscillations. The model simulates the experimental observations that high levels of mitochondrial ADP and ATP abolish the oscillations, as does inhibition of electron transport. The model makes predictions on the influence of pH and magnesium levels on metabolic oscillations.

The Ca 2+ leak paradox and rogue ryanodine receptors: SR Ca 2+ efflux theory and practice.

Ca(2+) efflux from the sarcoplasmic reticulum (SR) is routed primarily through SR Ca(2+) release channels (ryanodine receptors, RyRs). When clusters of RyRs are activated by trigger Ca(2+) influx through L-type Ca(2+) channels (dihydropyridine receptors, DHPR), Ca(2+) sparks are observed. Close spatial coupling between DHPRs and RyR clusters and the relative insensitivity of RyRs to be triggered by Ca(2+) together ensure the stability of this positive-feedback system of Ca(2+) amplification. Despite evidence from single channel RyR gating experiments that phosphorylation of RyRs by protein kinase A (PKA) or calcium-calmodulin dependent protein kinase II (CAMK II) causes an increase in the sensitivity of the RyR to be triggered by [Ca(2+)](i) there is little clear evidence to date showing an increase in Ca(2+) spark rate. Indeed, there is some evidence that the SR Ca(2+) content may be decreased in hyperadrenergic disease states. The question is whether or not these observations are compatible with each other and with the development of arrhythmogenic extrasystoles that can occur under these conditions. Furthermore, the appearance of an increase in the SR Ca(2+) "leak" under these conditions is perplexing. These and related complexities are analyzed and discussed in this report. Using simple mathematical modeling discussed in the context of recent experimental findings, a possible resolution to this paradox is proposed. The resolution depends upon two features of SR function that have not been confirmed directly but are broadly consistent with several lines of indirect evidence: (1) the existence of unclustered or "rogue" RyRs that may respond differently to local [Ca(2+)](i) in diastole and during the [Ca(2+)](i) transient; and (2) a decrease in cooperative or coupled gating between clustered RyRs in response to physiologic phosphorylation or hyper-phosphorylation of RyRs in disease states such as heart failure. Taken together, these two features may provide a framework that allows for an improved understanding of cardiac Ca(2+) signaling.

Local Ca(2+) signaling and EC coupling in heart: Ca(2+) sparks and the regulation of the [Ca(2+)](i) transient.

The elementary event of Ca(2+) release in heart is the Ca(2+) spark. It occurs at a low rate during diastole, activated only by the low cytosolic [Ca(2+)](i). Synchronized activation of many sparks is due to the high local [Ca(2+)](i) in the region surrounding the sarcoplasmic reticulum (SR) Ca(2+) release channels and is responsible for the systolic [Ca(2+)](i) transient. The biophysical basis of this calcium signaling is discussed. Attention is placed on the local organization of the ryanodine receptors (SR Ca(2+) release channels, RyRs) and the other proteins that underlie and modulate excitation-contraction (EC) coupling. A brief review of specific elements that regulate SR Ca(2+) release (including SR lumenal Ca(2+) and coupled gating of RyRs) is presented. Finally integrative calcium signaling in heart is presented in the context of normal heart function and heart failure.