Na + -Ca 2+ Exchange

The contraction of cardiac muscle is initiated by the influx of Ca2+ through voltage-sensitive Ca2+ channels. Some of the Ca2+ entering the cell binds to Ca2+ release channels (ryanodine receptors) on the sarcoplasmic reticulum (SR) and triggers a release of Ca2+ from the SR. After the subsequent contraction, Ca2+ must be removed from the myoplasm to facilitate relaxation. Most Ca2+ is pumped back into the SR, but a significant fraction is extruded from the cell by the Na+-Ca2+ exchanger. In the steady state, the amount of Ca2+ leaving the cell via the exchanger equals the amount of Ca2+ that enters through Ca2+ channels.1,2⇓This simple framework explains general aspects of cardiac excitation-contraction coupling but, of course, there are complications and controversy. Some of the controversy revolves around the exact role of the Na+-Ca2+ exchanger in this scenario. The exchanger can transport Ca2+ in either direction across the cell membrane and possibly sometimes mediates Ca2+ influx. The direction of net Ca2+ transport is determined by three factors: the Na+ gradient, the Ca2+ gradient, and the membrane potential. During the early phases of the action potential, for example, depolarization favors reversal of the exchanger into the Ca2+ influx mode. On the other hand, Ca2+ will be rising rapidly at this time as a result of channel openings and SR Ca2+ release. An increased intracellular Ca2+ level will push the exchanger back into the Ca2+ efflux mode.So, does the Na+-Ca2+ exchanger contribute significantly to Ca2+ influx? Attempts to address this question are not straightforward. The primary problem is that experiments to address the issue typically use pharmacological or ionic interventions …