Bimodal regulation of Na(+)--Ca(2+) exchanger by beta-adrenergic signaling pathway in shark ventricular myocytes.
In shark heart, the Na(+)--Ca(2+) exchanger serves as a major pathway for both Ca(2+) influx and efflux, as there is only rudimentary sarcoplasmic reticulum in these hearts. The modulation of the exchanger by a beta-adrenergic agonist in whole-cell clamped ventricular myocytes was compared with that of the Na(+)--Ca(2+) exchanger blocker KB-R7943. Application of 5 microM isoproterenol and 10 microM KB-R7943 suppressed both the inward and the outward Na(+)--Ca(2+) exchanger current (I(Na--Ca)). The isoproterenol effect was mimicked by 10 microM forskolin. Isoproterenol and forskolin shifted the reversal potential (E(rev)) of I(Na--Ca) by approximately -23 mV and -30 mV, respectively. An equivalent suppression of outward I(Na--Ca) by KB-R7943 to that by isoproterenol produced a significantly smaller shift in E(rev) of about --4 mV. The ratio of inward to outward exchanger currents was also significantly larger in isoproterenol- than in control- and KB-R7943-treated myocytes. Our data suggest that the larger ratio of inward to outward exchanger currents as well as the larger shift in E(rev) with isoproterenol results from the enhanced efficacy of Ca(2+) efflux via the exchanger. The protein kinase A-mediated bimodal regulation of the exchanger in parallel with phosphorylation of the Ca(2+) channel and enhancement of its current may have evolved to satisfy the evolutionary needs for accelerated contraction and relaxation in hearts of animals with vestigial sarcoplasmic Ca(2+) release stores.
Woo
S H
SH
Department of Pharmacology, Georgetown University School of Medicine, Washington, DC 20007, USA.
Morad
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D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004594:Electrophysiology; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D012754:Sharks; D015398:Signal Transduction / Q000502:physiology*; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D016276:Ventricular Function
C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D019831:Sodium-Calcium Exchanger; D013890:Thiourea; D007545:Isoproterenol