Allosteric Activation of Na[super]+-Ca[super]2+ Exchange by L-Type Ca[super]2+ Current Augments the Trigger Flux for SR Ca[super]2+ Release in Ventricular Myocytes

The possible contribution of Na[super]+-Ca[super]2+ exchange to the triggering of Ca[super]2+ release from the sarcoplasmic reticulum in ventricular cells remains unresolved. To gain insight into this issue, we measured the "trigger flux" of Ca[super]2+ crossing the cell membrane in rabbit ventricular myocytes with Ca[super]2+ release disabled pharmacologically. Under conditions that promote Ca[super]2+ entry via Na[super]+-Ca[super]2+ exchange, internal [Na[super]+] (10 mM), and positive membrane potential, the Ca[super]2+ trigger flux (measured using a fluorescent Ca[super]2+ indicator) was much greater than the Ca[super]2+ flux through the L-type Ca[super]2+ channel, indicating a significant contribution from Na[super]+-Ca[super]2+ exchange to the trigger flux. The difference between total trigger flux and flux through L-type Ca[super]2+ channels was assessed by whole-cell patch-clamp recordings of Ca[super]2+ current and complementary experiments in which internal [Na[super]+] was reduced. However, Ca[super]2+ entry via Na[super]+-Ca[super]2+ exchange measured in the absence of L-type Ca[super]2+ current was considerably smaller than the amount inferred from the trigger flux measurements. From these results, we surmise that openings of L-type Ca[super]2+ channels increase [Ca[super]2+] near Na[super]+-Ca[super]2+ exchanger molecules and activate this protein. These results help to resolve seemingly contradictory results obtained previously and have implications for our understanding of the triggering of Ca[super]2+ release in heart cells under various conditions.