PT - JOURNAL ARTICLE AU - Christoph H. Kindler AU - Matthias Paul AU - Hilary Zou AU - Canhui Liu AU - Bruce D. Winegar AU - Andrew T. Gray AU - C. Spencer Yost TI - Amide Local Anesthetics Potently Inhibit the Human Tandem Pore Domain Background K<sup>+</sup> Channel TASK-2 (KCNK5) AID - 10.1124/jpet.103.049809 DP - 2003 Jul 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 84--92 VI - 306 IP - 1 4099 - http://jpet.aspetjournals.org/content/306/1/84.short 4100 - http://jpet.aspetjournals.org/content/306/1/84.full SO - J Pharmacol Exp Ther2003 Jul 01; 306 AB - Blockade of voltage-gated sodium (Na+) channels by local anesthetics represents the main mechanism for inhibition of impulse propagation. Local anesthetic-induced potassium (K+) channel inhibition is also known to influence transmission of sensory impulses and to potentiate inhibition. K+ channels involved in this mechanism may belong to the emerging family of background tandem pore domain K+ channels (2P K+ channels). To determine more precisely the effects of local anesthetics on members of this ion channel family, we heterologously expressed the 2P K+ channels TASK-2 (KCNK5), TASK-1 (KCNK3), and chimeric TASK-1/TASK-2 channels in oocytes of Xenopus laevis. TASK-2 cDNA-transfected HEK 293 cells were used for single-channel recordings. Local anesthetic inhibition of TASK-2 was dose-dependent, agent-specific, and stereoselective. The IC50 values for R-(+)-bupivacaine and S-(–)-bupivacaine were 17 and 43 μM and for R-(+)-ropivacaine and S-(–)-ropivacaine, 85 and 236 μM. Lidocaine (1 mM) inhibited TASK-2 currents by 55 ± 4%, whereas its quaternary positively charged analog N-ethyl lidocaine (QX314) had no effect. Bupivacaine (100 μM) decreased channel open probability from 20.8 ± 1.6% to 5.6 ± 2.2%. Local anesthetics [300 μM R-(+)-bupivacaine] caused significantly greater depolarization of the resting membrane potential of TASK-2-expressing oocytes compared with water-injected control oocytes (15.8 ± 2.5 mV versus 0.1 ± 0.05 mV; p &lt; 0.001). Chimeric TASK-1/TASK-2 2P K+ channel subunits that retained pH sensitivity demonstrated that the carboxy domain of TASK-2 mediates the greater local anesthetic sensitivity of TASK-2. These results show that clinically achievable concentrations of local anesthetics inhibit background K+ channel function and may thereby enhance conduction blockade. The American Society for Pharmacology and Experimental Therapeutics