Regulation of cardiac sodium-calcium exchanger by β-adrenergic agonists

Abstract

Na+-Ca2+ exchanger and Ca2+ channel are two major sarcolemmal Ca2+- transporting proteins of cardiac myocytes. Although the Ca2+ channel is effectively 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 down- regulates the Na+-Ca2+ exchanger, independent of intracellular Ca2+ and membrane potential, by activation of the β-receptor/adenylate-cyclase/cAMP- dependent cascade, resulting in suppression of transmembrane Ca2+ transport via the exchanger and providing for the well-documented contracture- suppressant effect of the hormone on frog heart. The β-blocker propranalol blocks the isoproterenol effect, whereas forskolin, cAMP, and theophylline mimic it. In the frog heart where contractile Ca2+ is transported primarily by the Na+-Ca2+ exchanger, the β-agonists' simultaneous enhancement of Ca2+ current, I(Ca), and suppression of Na+-Ca2+ exchanger current, I(Na-Ca), would enable the myocyte to develop force rapidly at the onset of depolarization (enhancement of I(Ca)) 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 sarcoplasmic reticulum Ca2+- ATPase/phospholamban complex and absence of significant intracellular Ca2+ release pools in the frog heart.