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Involvement of calcium in pacemaker firing

D.G. Allen,1 J. Liu,1 M.S. Imtiaz2 and Y.K. Ju,1 1Discipline of Physiology, School of Medical Sciences, University of Sydney, NSW 2006, Australia and 2School of Biomedical Sciences, University of Newcastle, Callaghan, NSW 2308, Australia.

Pacemaker firing in the heart was initially considered to result from the coupled activity of a series of voltage-sensitive channels (voltage clock). The discovery that ryanodine, a blocker of sarcoplasmic reticulum (SR) Ca2+ release, slowed or stopped pacemaker firing first suggested that intracellular Ca2+ contributed to the process (calcium clock). Ju & Allen (1998) suggested that Ca2+ released from the SR was extruded from the cell on the Na/Ca exchanger and that this process generated an inward current that contributed to the pacemaker potential primarily during early diastole. Lakatta and his group (Vinogradova et al., 2004) focused on Ca2+ sparks, which occur only when the Ca2+ content of the SR is high and therefore in late in diastole, and showed that the close localization of Ca2+ release sites and Na/Ca exchangers led to a component of inward current late in diastole.

We have recently discovered two other Ca2+ pathways in pacemaker cells with potential roles in Ca2+ regulation and therefore firing rate. Pacemaker cells, like most cell types, possess a store-operated Ca2+ current (Ju et al., 2007) which provides Ca2+ influx, and presumably an inward current, whenever the store is sufficiently depleted of Ca2+. Whether this current is turned on briefly at the end of each systole or whether it is background current which reflects the time-averaged level of Ca2+ in the SR is currently unknown. When the store is depleted and the store-operated Ca2+ current is activated, the effect on firing rate is likely to be complex because simultaneously the SR Ca2+ release will be reduced and therefore Na/Ca related current small whereas the store-operated Ca2+ current will be turned on. Thus the net effect on firing rate is not intuitively obvious.

A second novel Ca2+ pathway in pacemaker cells is provided by IP3 receptors which we recently showed to be present in the SR of pacemaker cells (Ju et al., 2011). The main Ca2+ release channel in cardiac SR is the ryanodine receptor (RyR2) which is Ca2+-sensitive and activated by the Ca2+ influx through the L-type Ca2+ channels in the surface membrane. In contrast IP3 receptors (IP3 R2) are ∼50 fold less frequent and activated by IP3 but not by Ca2+. Nevertheless we have shown that IP3 agonist and antagonists, increase or decrease the firing rate, respectively, and that these effects are absent in IP3 R2 KO mice (Ju et al., 2011).

One challenge for these novel Ca2+ pathways is to determine whether they make a contribution to the normal firing rate and, if so, under what circumstances. The pharmacological and genetic tools for analysing these contributions are imperfect, so an alternative is to use mathematical modelling. We have added a store-operated Ca2+ channel (Allen et al., 2012) to an existing pacemaker model (Imtiaz et al., 2010) and explored the effects on firing rate. We have also added IP3 receptors to the SR in the model and have demonstrated how their presence modulates Ca2+ handling and pacemaker firing rate.

Allen DG, Ju YK, Liu J, & Imtiaz M (2012). In Store-operated Ca2+ entry pathways, eds. Groschner K, Graier WF, & Romanin C, Springer, Wien, Austria.

Imtiaz MS, von der Weid PY, Laver DR, & Van Helden DF (2010). Journal of Molecular and Cellular Cardiology 49, 412-426.

Ju YK & Allen DG (1998). Journal of Physiology 508, 153-166.

Ju YK, Chu Y, Chaulet H, Lai D, Gervasio OL, Graham RM, Cannell MB, & Allen DG (2007). Circulation Resesearch 100, 1605-1614.

Ju YK, Liu J, Lee BH, Lai D, Woodcock EA, Lei M, Cannell MB, & Allen DG (2011). Circulation Resesearch 109, 848-857.

Vinogradova TM, Zhou YY, Maltsev V, Lyashkov A, Stern M, & Lakatta EG (2004). Circulation Resesearch 94, 802-809.

We gratefully acknowledge financial supported from the NHMRC.