A Trek-Like K+ Channel Current Inhibited by Norepinephrine in Rat Atrial Myocytes

Accumulating evidence indicates that two-pore domain K+ (K2P) channels contribute to atrial background K+ currents. Atrial background K+ currents are modulated by norepinephrine (NE). However, the identity of the underlying channels and the mechanisms of their modulation remain unclear. This study aimed to investigate the norepinephrinergic modulation of rat atrial K+ currents. Whole-cell rat atrial myocyte currents were recorded at 36°C. NE (1 μM) increased L-type Ca2+ current (ICaL) by 205±40 % (n=6) and inhibited the steady-state outward current (IKss) by 42.1±4.3 % (n=7). The NE-dependent inhibition of IKss was: abolished by blockers of the K2P channel, TREK-1 (K2P2.1), fluoxetine (100 μM) and mibefradil (2.5 μM), partially reduced by 4-aminopyridine (3 mM, 14.6±2.7 %, n=5; P<0.0001) and unaffected by blockers of the K2P channels, TASK-1 (K2P3.1) and TASK-3 (K2P3.3), Zn2+ (1 mM). Conversely, NE-dependent inhibition of IKss was potentiated (60.9±3.9 %, n=5; P<0.01) by the arachidonic acid analogue, EYTA (10 μM). Noise analysis revealed a unitary conductance of 33.0±7.5 pS for the NE-sensitive channel (n=8). Theeffectof 1 μM NE on IKss was abolished by β1/β2-adrenoceptor non-selective propranolol (1 μM). The action of NE on IKss, but not ICaL, was abolished by pertussis toxin-treatment. NE prolonged APD30 by 52±19 % (n=5; P<0.05). In conclusion, NE inhibits a TREK-like K+ channel current via a pertussis toxin-sensitive pathway that contributes to action potential prolongation in rat atrial myocytes.