Projects and Grants
Effective pumping of blood by the heart depends on complex interactions between electrical and calcium signaling systems within heart cells. Each time the heart beats, current flowing through the ion channels in the plasma membrane changes the voltage across the cell membrane. This induces the opening of channels selective for calcium, which allow calcium ions to enter the cell. These calcium ions in turn causes the release of a much larger amount of calcium from an intracellular organelle known as the sarcoplasmic reticulum (SR). This process, known as calcium-induced calcium release is the key event linking electrical excitation to contraction of the heart. Mis-regulation of this process can contribute to pathological function in disease states such as heart failure, but the precise molecular defects that cause particular clinical observations are not well-understood. Thus, studies that produce a more thorough, quantitative understanding of calcium handling in the heart may lead to the identification of new targets for therapies. Several projects underway in the laboratory are aimed at understanding the regulation of calcium-induced calcium release and the interactions between electrical and calcium signals in heart cells.
- Termination and recovery of calcium release
Calcium-induced calcium release displays intrinsic positive feedback in that released calcium can trigger the additional release. Despite this autocatalysis, which in principle could allow release to continue indefinitely, the individual units of calcium release, calcium sparks, last less than 50 milliseconds.
The nature of the strong inhibitory mechanism that ensures robust termination of these events remains largely unknown. We are actively investigating this question, along with the closely related issue of recovery after release terminates. Figure 1, for instance, displays a confocal line scan image of repetitive calcium sparks induced in a rat ventricular myocyte pharmacologically (A). Analysis of such data (B and C) provides estimates of the time course of recovery of calcium spark amplitude and triggering probability. These results are consistent with the hypothesis that local depletion of calcium within intracellular stores controls the termination, and recovery after termination, of calcium release in heart cells.
- Conditions required for calcium waves
Under certain pathological conditions, calcium release is not well-controlled, and spontaneous calcium sparks can trigger additional sparks, resulting in a regenerative, propagating "calcium wave." Calcium waves promote asynchronous contraction of the heart and influence cellular electrical activity through the calcium-dependence of membrane ionic currents and transporters. Via the latter effect these events are thought to be potential triggers for lethal cardiac arrhythmias such as ventricular fibrillation. Both computational and experimental studies in the laboratory are aimed at understanding the factors that cause heart cells to enter this unstable state.
Figure 2 shows three examples of calcium release in a heart cell induced by localized flash photolysis of caged calcium. A regenerative calcium wave is only initiated in Figure 2C, indicating that this unstable mode of calcium release depends on the experimental conditions.
- A novel mathematical approach to modeling calcium release
In collaboration with Dr.'s Gregory Smith (William and Mary) and Saleet Jafri (George Mason), we are developing a new mathematical representation of calcium induced calcium release in heart cells. By using a probability density approach, we aim to develop a computationally efficient model that captures stochastic aspects of the triggering of calcium sparks.
Figure 3 shows snapshots of local calcium concentration distributions, within the cytosol and the SR, during calcium-induced calcium release. The different distributions observed confirm that these concentrations depend on the states of the cell membrane and SR channels that control this process. By computing the probability densities that produce correspond to these distributions directly, our novel model will avoid the computationally demanding task of simulating the stochastic triggering of calcium sparks using Monte-Carlo methods.
Eric A. Sobie, PhD
Icahn Medical Institute
12th Floor, Room 12-70F (Office)
1425 Madison Avenue
New York NY 10029