Evidence for Edg-3 Receptor-Mediated Activation ofIK.ACh by Sphingosine-1-Phosphate in Human Atrial Cardiomyocytes
- Herbert M. Himmel1,1,
- Dagmar Meyer zu Heringdorf1,3,
- Eva Graf1,
- Dobromir Dobrev1,
- Ariane Kortner2,
- Stephan Schüler2,
- Karl H. Jakobs3 and
- Ursula Ravens1
- 1Institut für Pharmakologie und Toxikologie (H.M.H., E.G., D.D., U.R.) and 2Herzzentrum (A.K., S.S.), Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; and 3Institut für Pharmakologie, Universitätsklinikum Essen, Essen, Germany (K.H.J., D.M.z.H.)
Abstract
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 ofIK.ACh in freshly isolated guinea pig, mouse, and human atrial myocytes. SPP activatedIK.ACh in atrial myocytes from all three species with a similar nanomolar potency (EC50 values: 4–8 nM). At these low concentrations, SPPC also activatedIK.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 ofEdg-1, Edg-3, and Edg-5were detected in human atrial cells. Moreover, activation ofIK.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.
Footnotes
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Send reprint requests to: Dr. Herbert M. Himmel, Institut für Pharmakologie und Toxikologie, Medizinische Fakultät Carl Gustav Carus, TU Dresden, Karl-Marx-Straβe 3, D-01109 Dresden, Germany. E-mail: himmel{at}rcs.urz.tu-dresden.de
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↵1 These authors contributed equally to this work.
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This work was supported in part by the Deutsche Forschungsgemeinschaft (Grant ME 1734/1 to D.M.z.H.).
- Abbreviations:
- SPP
- sphingosine-1-phosphate
- [Ca2+]i
- cytosolic free Ca2+concentration
- C8-ceramide-1-P
- N-octanoyl ceramide-1-phosphate
- Erev
- reversal potential
- dihydro-SPP
- dihydrosphingosine-1-phosphate
- IK1
- inward rectifier K+current
- IK.ACh
- muscarinic receptor-activated inward rectifier K+ current
- LPA
- lysophosphatidic acid
- SPPC
- sphingosylphosphorylcholine
- PCR
- polymerase chain reaction
- bp
- base pairs
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- Received December 29, 1999.
- Accepted May 16, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
