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

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 (EC50 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.