REGULATION OF CARDIAC SODIUM-CALCIUM EXCHANGER BY BETA-ADRENERGIC AGONISTS

Na+-Ca2+ exchanger and Ca2+ channel are two major sarcolemmal Ca2+-tra nsporting proteins of cardiac myocytes. Although the Ca2+ channel is e ffectively regulated by protein kinase A-dependent phosphorylation, no enzymatic regulation of the exchanger protein has been identified as yet. Here we report that in frog ventricular myocytes, isoproterenol d own-regulates the Na+-Ca2+ exchanger, independent of intracellular Ca2 + and membrane potential, by activation of the beta-receptorladenylate -cyclase/cAMP-dependent cascade, resulting in suppression of transmemb rane Ca2+ transport via the exchanger and providing for the well-docum ented contracture-suppressant effect of the hormone on frog heart. The beta-blocker propranalol blocks the isoproterenol effect, whereas for skolin, cAMP, and theophylline mimic it. In the frog heart where contr actile Ca2+ is transported primarily by the Na+-Ca2+ exchanger, the be ta-agonists' simultaneous enhancement of Ca2+ current, I-Ca, and suppr ession of Na+-Ca2+ exchanger current, I-Na-Ca, would enable the myocyt e to develop force rapidly at the onset of depolarization (enhancement of Ic,) and to decrease Ca2+ influx (suppression of I-Na-Ca) later in the action potential. This unique adrenergically induced shift in the Ca2+ influx pathways may have evolved in response to paucity of the s arcoplasmic reticulum Ca2+-ATPase/phospholamban complex and absence of significant intracellular Ca2+ release pools in the frog heart.