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Programme
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A specialized group of cells in the heart, known as the sinoatrial node (SAN), generates a pacemaker current that drives rhythmic beating of the heart. It is known that release and uptake of Ca2+ by the sarcoplasmic reticulum (SR) contributes to the cardiac rhythm under resting and stimulated conditions (Lakatta et al., 2003; Imtiazet al., 2010). During adrenergic stimulation an increase in both release of Ca2+ through the ryanodine receptors (RyR2) and uptake by SERCA accelerates heart rate. Transgenic animals lacking adrenergic stimulation of the SERCA with intact RyR2 lose adrenergic-stimulated increase in heart rate (Luo et al., 1994). This suggests that RyR2 alone has no significant role in adrenergic-stimulated increase in heart rate. However, in contradiction, knock-out mice lacking adrenergic stimulation of SERCA are able to produce half the increase in heart rate compared to wild type animals, thus indicating RyR2 has a role in accelerating heart rate (Kushnir et al., 2010; Shan et al., 2010). Thus, the relative contributions and mechanisms of SR uptake and release during adrenergic stimulation are not well understood. Furthermore, the contribution of other sources and sinks of Ca2+, such as the store-operated Ca2+ entry (SOCE) to SAN rhythm generation is not well understood. We have used mathematical modelling to investigate the relative contributions of RyR2, SERCA and SOCE in setting resting and adrenergic stimulated SAN rhythm.
The main results of our study are: 1) Our simulations agree with the experimental data in the literature on knock-out and transgenic animals and provide insight into mechanisms underlying the contradictory observations: a) Adrenergic-stimulation of RyR2 alone (compared to normal full stimulation) caused only half the increase in SAN frequency because of lower store load and reduced efficacy of sodium-Ca2+ exchange current (INCX); b) Adrenergic-stimulation of SERCA alone also caused only half the increase in SAN frequency. This is because unstimulated RyR resulted in reduced SR excitability resulting in delayed release of Ca2+ from the RyR2, which reduced SR contribution to the late diastolic phase. 2) The relative timing of Ca2+ entry through store-operated Ca2+ channel determines the effectiveness of SOCE in accelerating SAN frequency.
The results of this investigation indicate that SAN dynamics emerges due to symbiotic interaction between ionic channels, Ca2+ uptake and release, and store-operated Ca2+ entry.
Lakatta, E.G., Maltsev, V.A., Bogdanov, K.Y., Stern, M.D. & Vinogradova, T.M. (2003) Cyclic variation of intracellular calcium: a critical factor for cardiac pacemaker cell dominance. Circulation Research 92, e45-50.
Imtiaz, M.S., von der Weid, P.Y. & van Helden, D.F. (2010) Synchronization of Ca2+ oscillations: a coupled oscillator-based mechanism in smooth muscle. FEBS Journal 277, 278-285.
Luo W, Grupp IL, Harrer J, Ponniah S, Grupp G, Duffy JJ, Doetschman T, Kranias EG. (1994) Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of β-agonist stimulation. Circulation Research 75, 401-409.
Kushnir, A., Shan, J., Betzenhauser, M.J., Reiken, S. & Marks, A.R. Role of CaMKIIdelta phosphorylation of the cardiac ryanodine receptor in the force frequency relationship and heart failure. Proceedings of the National Academy of Sciences USA 107, 10274-10279 (2010).
Shan J, Kushnir A, Betzenhauser MJ, Reiken S, Li J, Lehnart SE, Lindegger N, Mongillo M, Mohler PJ, Marks AR. (2010) Phosphorylation of the ryanodine receptor mediates the cardiac fight or flight response in mice. Journal of Clinical Investigation 120, 4388-4398.