Evidence for Edg-3 receptor-mediated activation of I-K.ACh by sphingosine-1-phosphate in human atrial cardiomyocytes

Sphingosine-1-phosphate (SPP) and sphingosylphosphorylcholine (SPPC) have b een reported to activate muscarinic receptor-activated inward rectifier Kcurrent (I-K.ACh) in cultured guinea pig atrial myocytes with similar nanom olar potency. Members of the endothelial differentiation gene (Edg) recepto r family were recently identified as receptors for SPP; however, these rece ptors respond only to micromolar concentrations of SPPC. Here we investigat ed the sphingolipid-induced activation of I-K.ACh in freshly isolated guine a pig, mouse, and human atrial myocytes. SPP activated I-K.ACh in atrial my ocytes from all three species with a similar nanomolar potency (EC50 values : 4-8 nM). At these low concentrations, SPPC also activated I-K.ACh in guin ea pig myocytes. In contrast, SPPC was almost ineffective in mouse and huma n myocytes, thus resembling the pharmacology of the Edg receptors. Transcri pts of Edg-1, Edg-3, and Edg-5 were detected in human atrial cells. Moreove r, activation of I-K.ACh by SPP was blocked by the Edg-3-selective antagoni st 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-ind uced I-K.ACh activation in human atrial myocytes is mediated by the Edg-3 s ubtype of SPP receptors.