title: Evidence for Edg-3 receptor-mediated activation of I(K.ACh) by sphingosine-1-phosphate in human atrial cardiomyocytes.
abstract: Sphingosine-1-phosphate (SPP) and sphingosylphosphorylcholine (SPPC) have been reported to activate muscarinic receptor-activated inward rectifier K(+) current (I(K.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 I(K.ACh) in freshly isolated guinea pig, mouse, and human atrial myocytes. SPP activated I(K.ACh) in atrial myocytes from all three species with a similar nanomolar potency (EC(50) values: 4-8 nM). At these low concentrations, SPPC also activated I(K.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 I(K.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 I(K.ACh) activation by SPP and SPPC exhibits large species differences. Furthermore, they suggest that SPP-induced I(K.ACh) activation in human atrial myocytes is mediated by the Edg-3 subtype of SPP receptors.
authors.affiliation: Institut für Pharmakologie und Toxikologie, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. himmel@rcs.urz.tudresden.de
authors.forename: H M
authors.initials: HM
authors.lastname: Himmel
authors.forename: D
authors.initials: D
authors.lastname: Meyer Zu Heringdorf
authors.forename: E
authors.initials: E
authors.lastname: Graf
authors.forename: D
authors.initials: D
authors.lastname: Dobrev
authors.forename: A
authors.initials: A
authors.lastname: Kortner
authors.forename: S
authors.initials: S
authors.lastname: Schüler
authors.forename: K H
authors.initials: KH
authors.lastname: Jakobs
authors.forename: U
authors.initials: U
authors.lastname: Ravens
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins; D066298:In Vitro Techniques; D008246:Lysophospholipids; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D015221:Potassium Channels / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying; D049312:Receptors, Lysophospholipid; D013045:Species Specificity; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D008246:Lysophospholipids; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D049312:Receptors, Lysophospholipid; D000072000:NF-KappaB Inhibitor alpha; C060506:sphingosine 1-phosphate; D013110:Sphingosine