Control of intracellular Na(+) and Ca(2+) concentrations in rat cardiomyocytes - crosstalk between the Na(+)/K(+)-ATPase and the Na(+)/Ca(2+)-exchanger : crosstalk between the Na<eks>+/K<eks>+-ATPase and the Na<eks>+/ca<eks>2<eks>+-exchange

Cardiomyocyte contraction is controlled by the intracellular Ca2+ concentration ([Ca2+]i), which is regulated by L-type Ca2+ channels and by a Na+/Ca2+-exchanger. The Na+/Ca2+-exchanger translocates three Na+ and one Ca2+ in opposite directions over the sarkolemma. The activity of the Na+/Ca2+-exchanger is determined by the sarcolemmal Na+ gradient. This gradient is maintained by the Na+/K+-ATPase, which pumps three Na+ out of and two K+ into the cell. Since [Ca2+]i depends on [Na+]i, a crosstalk between the Na+/Ca2+-exchanger and the Na+/K+-ATPase via intracellular Na+ could be important for cardiomyocyte contractility. Recently, the existence of subsarcolemmal diffusions gradients for Na+ has been suggested. Such diffusion gradients would cause heterogeneous [Na+]i, and thus influence regulation of [Ca2+]i. The purpose of the present study was to examine whether subsarcolemmal diffusion gradients for Na+ permit functional interaction, or crosstalk, between the Na+/K+-ATPase and the Na+/Ca2+-exchanger. Whole-cell voltage clamp experiments were performed using low resistance patch pipettes that permit cell dialysis. The Na+/K+-ATPase and the Na+/Ca2+-exchanger were activated by the addition of 5.4 mM K+ and 2 mM Ca2+ to the external solution, respectively. At a holding potential of –50 mV, addition of 5.4 mM K+ activated a Na+/K+-ATPase current (INa/K) which peaked within ~2 s (2.44 ± 0.28 pA/pF). This current gradually decreased to a steady state-level within 2-3 min (1.50 ± 0.64 pA/pF). The Na+/Ca2+-exchanger current (INa/Ca) measured ~5 s after INa/K activation was reduced to 77 % of control. When INa/K reached a steady-state, INa/Ca was reduced to 40 % of control. The reduction in INa/Ca was proportional to the reduction in INa/K, suggesting crosstalk between the two proteins via subsarcolemmal Na+. In conclusion, subsarcolemmal concentration gradients for Na+ influence the crosstalk between the Na+/K+-ATPase and the Na+/Ca2+-exchanger. Adequate regulation of this crosstalk could be important for regulation of cardiac contractility