Regulation of cardiac sodium-calcium exchanger by beta-adrenergic agonists.
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 beta-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 beta-blocker propranolol 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 beta-agonists' simultaneous enhancement of Ca2+ current, ICa, and suppression of Na+-Ca2+ exchanger current, INa-Ca would enable the myocyte to develop force rapidly at the onset of depolarization (enhancement of ICa) and to decrease Ca2+ influx (suppression of INa-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.
Fan
J
J
Department of Pharmacology, Georgetown University Medical Center, Washington, DC 20007, USA.
Shuba
Y M
YM
Morad
M
M
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006352:Heart Ventricles; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology*; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D009200:Myocardial Contraction; D009532:Nickel / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011433:Propranolol / Q000494:pharmacology; D011894:Rana pipiens; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000201:enzymology; D019831:Sodium-Calcium Exchanger; D013806:Theophylline / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D002352:Carrier Proteins; D011943:Receptors, Adrenergic, beta; D019831:Sodium-Calcium Exchanger; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D009532:Nickel; D011433:Propranolol; D013806:Theophylline; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D000252:Calcium-Transporting ATPases; D007545:Isoproterenol; D002118:Calcium