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

Abstract

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 α2β2, α2β4, α3β2, α3β4, α4β2 and α4β4), 5-hydroxytryptamine3 (5-HT3), α1β2γ(2s) γ-aminobutyric acid type A (GABA(A)) and α1 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 β4 subunits were more sensitive to ketamine and dizocilpine than those containing β2 subunits. The inhibitor concentration for half-maximal response (IC50) values for ketamine of hnAChRs composed of β4 subunits were 9.5-29 μM, whereas those of β2 subunits were 50-92 μM. Conversely, 5-HT3 receptors were inhibited only by concentrations of ketamine and dizocilpine higher than the anesthetic concentrations. This inhibition was mixed (competitive/noncompetitive). GABA(A) 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 β subunits being more critical than α subunits. Conversely, 5-HT3, GABA(A), and glycine receptors were relatively insensitive to dissociative anesthetics.