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Vol. 58, Issue 2, 449-454, August 2000

Evidence for Edg-3 Receptor-Mediated Activation of IK.ACh by Sphingosine-1-Phosphate in Human Atrial Cardiomyocytes

Herbert M. Himmel,1 Dagmar Meyer zu Heringdorf,1 Eva Graf, Dobromir Dobrev, Ariane Kortner, Stephan Schüler, Karl H. Jakobs, and Ursula Ravens

Institut für Pharmakologie und Toxikologie (H.M.H., E.G., D.D., U.R.) and Herzzentrum (A.K., S.S.), Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; and Institut für Pharmakologie, Universitätsklinikum Essen, Essen, Germany (K.H.J., D.M.z.H.)

Sphingosine-1-phosphate (SPP) and sphingosylphosphorylcholine (SPPC) have been reported to activate muscarinic receptor-activated inward rectifier K+ current (IK.ACh) in cultured guinea pig atrial myocytes with similar nanomolar potency. Members of the endothelial differentiation gene (Edg) receptor family were recently identified as receptors for SPP; however, these receptors respond only to micromolar concentrations of SPPC. Here we investigated the sphingolipid-induced activation of IK.ACh in freshly isolated guinea pig, mouse, and human atrial myocytes. SPP activated IK.ACh in atrial myocytes from all three species with a similar nanomolar potency (EC50 values: 4-8 nM). At these low concentrations, SPPC also activated IK.ACh in guinea pig myocytes. In contrast, SPPC was almost ineffective in mouse and human myocytes, thus resembling the pharmacology of the Edg receptors. Transcripts of Edg-1, Edg-3, and Edg-5 were detected in human atrial cells. Moreover, activation of IK.ACh by SPP was blocked by the Edg-3-selective antagonist suramin, which did not affect basal or carbachol-stimulated K+ currents. In conclusion, these data indicate that IK.ACh activation by SPP and SPPC exhibits large species differences. Furthermore, they suggest that SPP-induced IK.ACh activation in human atrial myocytes is mediated by the Edg-3 subtype of SPP receptors.

1 These authors contributed equally to this work.

Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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