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Allosteric Activation of Na⁺-Ca²⁺ Exchange by L-Type Ca²⁺ Current Augments the Trigger Flux for SR Ca²⁺ Release in Ventricular Myocytes

Eric A. Sobie ^*, Mark B. Cannell  and John H. B. Bridge 

^* Department of Pharmacology & Systems Therapeutics, Mount Sinai School of Medicine, New York, New York; Department of Physiology, University of Auckland, Auckland, New Zealand; and Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah

Correspondence: Address reprint requests and inquiries to John H. B. Bridge, Tel.: 801-581-8183; E-mail: bridge{at}cvrti.utah.edu.

The possible contribution of Na⁺-Ca²⁺ exchange to the triggering of Ca²⁺ release from the sarcoplasmic reticulum in ventricular cells remains unresolved. To gain insight into this issue, we measured the "trigger flux" of Ca²⁺ crossing the cell membrane in rabbit ventricular myocytes with Ca²⁺ release disabled pharmacologically. Under conditions that promote Ca²⁺ entry via Na⁺-Ca²⁺ exchange, internal [Na⁺] (10 mM), and positive membrane potential, the Ca²⁺ trigger flux (measured using a fluorescent Ca²⁺ indicator) was much greater than the Ca²⁺ flux through the L-type Ca²⁺ channel, indicating a significant contribution from Na⁺-Ca²⁺ exchange to the trigger flux. The difference between total trigger flux and flux through L-type Ca²⁺ channels was assessed by whole-cell patch-clamp recordings of Ca²⁺ current and complementary experiments in which internal [Na⁺] was reduced. However, Ca²⁺ entry via Na⁺-Ca²⁺ exchange measured in the absence of L-type Ca²⁺ current was considerably smaller than the amount inferred from the trigger flux measurements. From these results, we surmise that openings of L-type Ca²⁺ channels increase [Ca²⁺] near Na⁺-Ca²⁺ 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 Ca²⁺ release in heart cells under various conditions.