Local anesthetic inhibition of baseline potassium channels with two pore domains in tandem

Background: Recently, a new structural family of potassium channels charact erized by two pore domains in tandem within their primary amino acid sequen ce was identified. These tandem pore domain potassium channels are not gate d by voltage and appear to be involved in the control of baseline membrane conductances. The goal of this study was to identify mechanisms of local an esthetic action on these channels. Methods: Oocytes of Xenopus laevis were Injected with cRNA from five cloned tandem pore domain baseline potassium channels (TASK,TREK-1, TOK1, ORK1, a nd TWIK-1), and the effects of several local anesthetics on the heterologou sly expressed channels were assayed using two-electrode voltage-clamp and c urrent-clamp techniques. Results: Bupivacaine(1 mar) inhibited all studied tandem pore potassium cha nnels, with TASK inhibited most potently, The potency of inhibition was dir ectly correlated with the octanol: buffer distribution coefficient of the l ocal anesthetic, with the exception of tetracaine, to which TASK is relativ ely insensitive, The approximate 50% inhibitory concentrations of TASK were 709 mu M mepivacaine, 222 mu M lidocaine, 51 mu M R(+)-ropivacaine, 53 mu M S(-)-ropivacaine, 668 mu M tetracaine, 41 mu M bupivacaine, and 39 mu M e tidocaine, Local anesthetics (1 mu) significantly depolarized the resting m embrane potential of TASK cRNA-injected oocytes compared with saline-inject ed control oocytes (tetracaine 22 +/- 6 mV vs. 7 +/- 1 mV, respectively, an d bupivacaine 31 +/- 7 mV vs. 6 +/- 4 mV), Conclusions: Local anesthetics inhibit tandem pore domain baseline potassiu m channels, and they could depolarize the resting membrane potential of cel ls expressing these channels, Whether inhibition of these channels contribu tes to conduction blockade or to the adverse effects of local anesthetics r emains to be determined.