Abstract
It has been demonstrated that sphingosine–1–phosphate (S1P) elicits many cellular responses by binding to G–protein–coupled endothelial differentiation gene–encoded (Edg) receptors. In the heart, S1P activates the muscarinic K+ channel (IK,ACh) in sino–atrial (SA) node cells and thereby evokes negative chronotropic actions. In the present study we investigated the effect of S1P on the slowly activating component of delayed rectifier K+ current (IKs) in guinea–pig ventricular myocytes using the whole–cell patch–clamp technique. IKs was elicited by depolarizing voltage steps given from a holding potential of –50 mV to various levels up to +50 mV and the effect of S1P on IKs was assessed by measuring the amplitude of the tail current elicited upon return to the holding potential. External application of S1P in nanomolar to micromolar concentrations reversibly increased the amplitude of IKs with mean half–maximal concentration (K1/2) of 69.7 nM (n = 6). S1P at 1 μM evoked a maximal increase of IKs by a factor of 1.68±0.1 (n = 6). Preincubation of ventricular myocytes with pertussis toxin (PTX, 5 μg/mL) largely abolished the stimulatory action of S1P, suggesting that a G protein–coupled plasma membrane receptor for S1P is involved. Thus the present investigation identifies a novel extracellular signalling molecule that positively regulates IKs in mammalian ventricular myocytes. [Jpn J Physiol 54 Suppl:S126 (2004)]
