Objective Sphingosine-1-phosphate (S-1-P), a potent lysophospholipid mediator which is released from platelets during clotting, activates a G-protein-gated inwardly rectifying K⁺ current (GIRK) in atrial and sino-atrial node myocytes. We denote this current I_K(S-1-P). A similar GIRK, which is activated by acetylcholine (ACh) and denoted I_K(ACh), is expressed in atrium. It shortens the action potential duration (APD) and reduces the effective refractory period (ERP). We have examined the effect of S-1-P on APD in guinea pig atrial myocytes by characterizing the rectification properties of I_K(S-1-P) and evaluating whether I_K(S-1-P) and I_K(ACh) exhibit convergence/occlusion.

Methods Membrane potential and K⁺ currents were recorded from guinea pig atrial myocytes. Inwardly rectifying K⁺ currents were recorded using a ramp voltage clamp waveform between +30 to − 130mV from a holding potential of − 7mV. Agonist-induced current changes were obtained by subtracting the control current.

Results S-1-P (1 and 10nM) altered both passive and active properties of atrial myocytes. S-1-P increased the threshold current for excitation and decreased the time constant of the subthreshold electrotonic potentials. In addition, both APD₅₀ and APD₉₀ were decreased substantially. Voltage clamp analysis showed that the outward conductance of I_K(IR) (G_K(IR)out) was 134.8±11.3pS pF^{− 1} (n=19) in S-1-P (100nM), and 207.0±19.6pS pF^{− 1} (n=18) in ACh (10μM). The ratio of G_K(IR)out:G_K(IR)in was about 0.7 for both S-1-P and ACh. The EC₅₀ values for the activation of G_K(IR)out and G_K(IR)in by S-1-P were 1.6 and 1.3nM, respectively. Addition of S-1-P (100nM) after the effect of ACh (10μM) had developed fully caused very little additional change.

Conclusion I _K(S-1-P) is carried by weakly inwardly-rectifying K⁺ channels that are the same as those activated by ACh. This K⁺ current can markedly shorten APD in guinea pig atrial myocytes. This effect would be expected to increase the incidence of atrial rhythm disturbances.