Copyright © 2006, European Society of Cardiology
Sphingosine-1-phosphate effects on guinea pig atrial myocytes: Alterations in action potentials and K+ currents
aDepartments of Bioengineering and Medicine, University of California San Diego, La Jolla, California, USA
bDepartment of Clinical Pharmacy, School of Pharmaceutical Sciences, Toho University, Funabashi, Japan
* Corresponding author. Department of Bioengineering and Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0412, USA. Tel.: +1 858 822 4424; fax: +1 858 534 4535. Email address: wgiles{at}bioeng.ucsd.edu
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 IK(S-1-P). A similar GIRK, which is activated by acetylcholine (ACh) and denoted IK(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 IK(S-1-P) and evaluating whether IK(S-1-P) and IK(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 IK(IR) (GK(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 GK(IR)out:GK(IR)in was about 0.7 for both S-1-P and ACh. The EC50 values for the activation of GK(IR)out and GK(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 IK(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.
KEYWORDS Arrhythmia (mechanism); Atrial function; K-channel; Lipid signaling; Sphingosine-1-phosphate