Amide local anesthetics potently inhibit the human tandem pore domain background K+ channel TASK-2 (KCNK5).
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 micro M and for R-(+)-ropivacaine and S-(-)-ropivacaine, 85 and 236 micro M. 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 micro M) decreased channel open probability from 20.8 +/- 1.6% to 5.6 +/- 2.2%. Local anesthetics [300 micro M 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.
Kindler
Christoph H
CH
Attending Physician, Department of Anesthesia, University Clinics, Kantonsspital, CH-4031 Basel, Switzerland. ckindler@uhbs.ch
Paul
Matthias
M
Zou
Hilary
H
Liu
Canhui
C
Winegar
Bruce D
BD
Gray
Andrew T
AT
Yost
C Spencer
CS
D000577:Amides / Q000494:pharmacology; D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D002045:Bupivacaine / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D024683:Potassium Channels, Tandem Pore Domain / Q000037:antagonists & inhibitors*; D011993:Recombinant Fusion Proteins / Q000378:metabolism
D000577:Amides; D000779:Anesthetics, Local; C410295:KCNK5 protein, human; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D024683:Potassium Channels, Tandem Pore Domain; D011993:Recombinant Fusion Proteins; C420132:potassium channel subfamily K member 3; D002045:Bupivacaine