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CELLULAR AND MOLECULAR

Amide Local Anesthetics Potently Inhibit the Human Tandem Pore Domain Background K⁺ Channel TASK-2 (KCNK5)

Department of Anesthesia, University Clinics, Kantonsspital, Basel, Switzerland (C.H.K.); Department of Anesthesia and Operative Intensive Care Medicine, University of Köln, Köln, Germany (M.P.); and Department of Anesthesia and Perioperative Care, University of California, San Francisco, California (H.Z., C.L., B.D.W., A.T.G., C.S.Y.)

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 < 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.

Address correspondence to: Dr. Christoph H. Kindler, Attending Physician, Department of Anesthesia, University Clinics, Kantonsspital, CH-4031 Basel, Switzerland. E-mail: ckindler{at}uhbs.ch

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