Molecular mechanisms underlying ketamine-mediated inhibition of sarcolemmal adenosine triphosphate-sensitive potassium channels

Background: Ketamine inhibits adenosine triphosphate-sensitive potassium (K-ATP) channels, which results in the blocking of ischemic preconditioning in the heart and inhibition of vasorelaxation induced by K-ATP channel openers. in the current study, the authors investigated the molecular mechanisms of ketamine's actions on sarcolemmal. K-ATP channels that are reassociated by expressed subunits, inwardly rectifying potassium channels (Kir6.1 or Kir6.2) and sulfonylurea receptors (SUR1, SUR2A, or SUR2B). Methods: The authors used inside-out patch clamp configurations to investigate the effects of ketamine on the activities of reassociated Kir6.0/SUR channels containing wild-type, mutant, or chimeric SURs expressed in COS-7 cells. Results: Ketamine racemate inhibited the activities of the reassociated K-ATP channels in a SUR subtype-dependent manner: SUR2A/Kir6.2 (IC50 = 83 mum), SUR2B/Kir6.1 (IC50 = 77 mum), SUR2B/Kir6.2 (IC50 = 89 mum), and SUR1/Kir6.2 (IC50 = 1487 mum). S-(+)-ketamine was significantly less potent than ketamine racemate in blocking all types of reassociated K-ATP channels. The ketamine racemate and S-(+)-ketamine both inhibited channel currents of the truncated isoform of Kir6.2 (Kir6.2DeltaC36) with very low affinity. Application of 100 pm magnesium adenosine diphosphate significantly enhanced the inhibitory potency of ketamine racemate. The last transmembrane domain of SUR2 was essential for the full inhibitory effect of ketamine racemate. Conclusions: These results suggest that ketamine-induced inhibition of sarcolemmal K-ATP channels is mediated by the SUR subunit. These inhibitory effects of ketamine exhibit specificity for cardiovascular K-ATP channels, at least some degree of stereoselectivity, and interaction with intracellular magnesium adenosine diphospbate.