Subunit-dependent inhibition of human neuronal nicotinic acetylcholine receptors and other ligand-gated ion channels by dissociative anesthetics ketamine and dizocilpine

Anesthesiology. 2000 Apr;92(4):1144-53. doi: 10.1097/00000542-200004000-00033.


Background The neuronal mechanisms responsible for dissociative anesthesia remain controversial. N-methyl-D-aspartate (NMDA) receptors are inhibited by ketamine and related drugs at concentrations lower than those required for anesthetic effects. Thus, the authors studied whether ligand-gated ion channels other than NMDA receptors might display a sensitivity to ketamine and dizocilpine that is consistent with concentrations required for anesthesia.

Methods: Heteromeric human neuronal nicotinic acetylcholine receptors (hnAChR channels alpha2beta2, alpha2beta4, alpha3beta2, alpha3beta4, alpha4beta2 and alpha4beta4), 5-hydroxytryptamine3 (5-HT3), alpha1beta2gamma2S gamma-aminobutyric acid type A (GABAA) and alpha1 glycine receptors were expressed in Xenopus oocytes, and effects of ketamine and dizocilpine were studied using the two-electrode voltage-clamp technique.

Results: Both ketamine and dizocilpine inhibited hnAChRs in a noncompetitive and voltage-dependent manner. Receptors containing beta1 subunits were more sensitive to ketamine and dizocilpine than those containing beta2 subunits. The inhibitor concentration for half-maximal response (IC50) values for ketamine of hnAChRs composed of beta4 subunits were 9.5-29 microM, whereas those of beta2 subunits were 50-92 microM. Conversely, 5-HT3 receptors were inhibited only by concentrations of ketamine and dizocilpine higher than the anesthetic concentrations. This inhibition was mixed (competitive/noncompetitive). GABAA and glycine receptors were very resistant to dissociative anesthetics.

Conclusions: Human nAChRs are inhibited by ketamine and dizocilpine at concentrations possibly achieved in vivo during anesthesia in a subunit-dependent manner, with beta subunits being more critical than alpha subunits. Conversely, 5-HT3, GABAA, and glycine receptors were relatively insensitive to dissociative anesthetics.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Anesthetics, Dissociative / pharmacology*
  • Animals
  • Dizocilpine Maleate / pharmacology*
  • Electrophysiology
  • Excitatory Amino Acid Antagonists / pharmacology
  • GABA-A Receptor Antagonists
  • Humans
  • Ion Channel Gating / drug effects*
  • Ion Channels / drug effects*
  • Ketamine / pharmacology*
  • Ligands
  • Membrane Potentials / drug effects
  • Oocytes / metabolism
  • RNA, Messenger / biosynthesis
  • Receptors, Glycine / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, Nicotinic / drug effects*
  • Receptors, Serotonin / drug effects
  • Receptors, Serotonin, 5-HT3
  • Recombinant Proteins / metabolism
  • Serotonin Antagonists / pharmacology
  • Xenopus laevis


  • Anesthetics, Dissociative
  • Excitatory Amino Acid Antagonists
  • GABA-A Receptor Antagonists
  • Ion Channels
  • Ligands
  • RNA, Messenger
  • Receptors, Glycine
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Nicotinic
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT3
  • Recombinant Proteins
  • Serotonin Antagonists
  • Ketamine
  • Dizocilpine Maleate