A modelling study of the effects of ryanodine receptor gating on spontaneous action potential generation in heart ventricular cells

Elena Cocherová* and Alexandra Zahradníková

Institute of Molecular Physiology and Genetics, SAS, Bratislava, Slovakia

* elena.cocherova@savba.sk

Under normal conditions, the rapid onset of the action potential (AP) is a trigger of other processes related to release of calcium from the sarcoplasmic reticulum and to contraction in heart ventricular cells. During certain types of pathophysiologies, spontaneous action potentials can be generated not only by external physiological stimuli, but also by spontaneous calcium release that increases the activity of the sodium-calcium exchanger and thus leads to membrane depolarization.

To investigate the effect of ryanodine receptor (RyR) gating changes on spontaneous APs (sAPs) generation, we adapted the model of the rabbit ventricular myocyte from the Bers’ group (Shannon et al., 2005). The set of parameters related to the conditions of adrenergic stimulation in the original model included increased cytosolic Ca²⁺ sensitivity of the RyR, which led to generation of spontaneous APs at frequencies above 1 Hz, behaviour not observed experimentally. Therefore for simulations under conditions of adrenergic stimulation, the increase of RyR cytosolic Ca²⁺ sensitivity was omitted.

We have simulated the effects of RyR gating parameters: EC₅₀ of the cytoplasmic activation site (K_Ca^cyt); EC₅₀ of the luminal activation site (K_Ca^lum); maximum open probability in the absence of luminal Ca²⁺ activation (P_O^max(low Ca^lum)); maximum open probability in the presence of luminal Ca²⁺ activation (P_O^max(high Ca^lum)); open probability in the absence of cytosolic Ca²⁺ activation (P_O^min). For every parameter configuration, we let the simulation run for 300 s at the given stimulation frequency to obtain the stationary state. Then the external stimulation was stopped and the spontaneous APs were observed for 20 s. Pathological changes of RyR gating were simulated by an increase of a parameter to 500 % (P_O^min, P_O^max(high Ca^lum)) or a decrease to 20 % (K_Ca^cyt, K_Ca^lum, P_O^max(low Ca^lum)) of control. The effect of drugs altering RyR gating was simulated in the model as a change of one additional parameter in the opposite direction. We observed that spontaneous APs could be evoked by pathological RyR parameters and they could be eliminated by a concomitant change of a second parameter. For instance, an increase of K_Ca^lum eliminated spontaneous APs evoked by decreased K_Ca^cyt; an increase of K_Ca^cyt, K_Ca^lum or P_O^max(low Ca^lum) eliminated spontaneous APs evoked by increased P_O^min. However, certain parameters had practically no effect on the production of sAPs (e.g. a decrease of P_O^min or P_O^max(high Ca^lum) for sAPs evoked by decreased K_Ca^lum), pointing to a certain degree of specific complementary relations in RyR pathological states.

References

Shannon TR, Wang F, Bers DM. Regulation of cardiac sarcoplasmic reticulum Ca release by luminal [Ca] and altered gating assessed with a mathematical model. Biophys. J. 89: 4096 - 4110, 2005