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Regulation of cardiac sodium-calcium exchanger by beta-adrenergic agonists.

J. Fan, Y. Shuba, and M. Morad. Proc. Natl. Acad. Sci. U. S. A. 93 (11): 5527-32 (May 1996)

Abstract

Na$^+$-Ca$^2+$ exchanger and Ca$^2+$ channel are two major sarcolemmal Ca$^2+$-transporting proteins of cardiac myocytes. Although the Ca$^2+$ 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$^+$-Ca$^2+$ exchanger, independent of intracellular Ca$^2+$ and membrane potential, by activation of the beta-receptor/adenylate-cyclase/cAMP-dependent cascade, resulting in suppression of transmembrane Ca$^2+$ transport via the exchanger and providing for the well-documented contracture-suppressant effect of the hormone on frog heart. The beta-blocker propranolol blocks the isoproterenol effect, whereas forskolin, cAMP, and theophylline mimic it. In the frog heart where contractile Ca$^2+$ is transported primarily by the Na$^+$-Ca$^2+$ exchanger, the beta-agonists' simultaneous enhancement of Ca$^2+$ current, ICa, and suppression of Na$^+$-Ca$^2+$ exchanger current, INa-Ca would enable the myocyte to develop force rapidly at the onset of depolarization (enhancement of ICa) and to decrease Ca$^2+$ influx (suppression of INa-Ca) later in the action potential. This unique adrenergically induced shift in the Ca$^2+$ influx pathways may have evolved in response to paucity of the sarcoplasmic reticulum Ca$^2+$-ATPase/phospholamban complex and absence of significant intracellular Ca$^2+$ release pools in the frog heart.

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Fan_1996_5527
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