Modelling excitation-contraction coupling at cellular and molecular level
Alexandra Zahradníková*, Ivan Valent, Elena Cocherová and Ivan Zahradník
Institute of Molecular Physiology and
Genetics, Slovak
* alexandra.zahradnikova@savba.sk
The main function of cardiac myocytes is to contract in response to calcium release evoked by the action potential. According to the local control theory, cellular calcium release is the summation of independent elementary calcium release events occurring at individual dyads – sites of close apposition of the voltage-dependent calcium channels of the plasma membrane (DHPRs) and couplons – clusters of calcium release channels (RyRs) of the junctional face membrane of the sarcoplasmic reticulum terminal cisternae. DHPRs open in response to membrane depolarization, whereby a small amount of Ca2+ ions enters the dyadic space and activates the juxtaposed RyRs, resulting in a calcium spark. Calcium sparks occur also in the absence of electrical stimulation at a very low rate, resulting in diastolic calcium release (see Cheng and Lederer, 2008 for review).
The process of RyR activation during the calcium spark is not clear (Cheng and Lederer, 2008). Here we present the bottom up approach to modeling of the processes leading to spark activation starting from single-channel RyR gating. Spontaneous calcium spark activation is modeled as a direct consequence of a single spontaneous RyR opening. To achieve consistency of the model with the calcium dependence of single-channel RyR activity and calcium spark frequency and with the distribution of spark calcium release flux amplitudes observed in experiments, both interaction of the RyR channels with Ca2+ and Mg2+ ions at the activation sites, their interaction with Mg2+ at the inhibition site, and allosteric coupling between ion binding and channel opening have to be accounted for.
This model can explain the observations in cardiac pathologies, such as heart failure or arrhythmogenic RyR mutations, namely the increased diastolic spark rate and the increased propensity to generation of arrhythmogenic calcium waves, on the basis of changes in RyR gating.
References
Cheng H, Lederer WJ. Calcium sparks. Physiol Rev 88: 1491-1545, 2008.