Interplay between SERCA and sarcolemmal Ca$^2+$ efflux pathways controls spontaneous release of Ca$^2+$ from the sarcoplasmic reticulum in rat ventricular myocytes.
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J. Physiol. 559 (Pt 1): 121--128 (August 2004)

Waves of calcium-induced calcium release occur in a variety of cell types and have been implicated in the origin of cardiac arrhythmias. We have investigated the effects of inhibiting the SR Ca$^2+$-ATPase (SERCA) with the reversible inhibitor 2',5'-di(tert-butyl)-1,4-benzohydroquinone (TBQ) on the properties of these waves. Cardiac myocytes were voltage clamped at a constant potential between -65 and -40 mV and spontaneous waves evoked by increasing external Ca$^2+$ concentration to 4 mm. Application of 100 microm TBQ decreased the frequency of waves. This was associated with increases of resting Ca$^2+$(i), the time constant of decay of Ca$^2+$(i) and the integral of the accompanying Na$^+$-Ca$^2+$ exchange current. There was also a decrease in propagation velocity of the waves. There was an increase of the calculated Ca$^2+$ efflux per wave. The SR Ca$^2+$ content when a wave was about to propagate decreased to 91.7 +/- 3.2\%. The period between waves increased in direct proportion to the Ca$^2+$ efflux per wave meaning that TBQ had no effect on the Ca$^2+$ efflux per unit time. We conclude that (i) decreased wave frequency is not a direct consequence of decreased Ca$^2+$ pumping by SERCA between waves but, rather, to more Ca$^2+$ loss on each wave; (ii) inhibiting SERCA increases the chance of spontaneous Ca$^2+$ release propagating at a given SR content.
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