Intravenous anesthetics differentially modulate ligand-gated ion channels

Background: Heteromeric neuronal nicotinic acetylcholine receptors (nAChRs) are potently inhibited by volatile anesthetics, but it is not known whether they are affected by intravenous anesthetics. Ketamine potentiates gamma-aminobutyric acid type A (GABA(A)) receptors at high concentrations, but it is unknown whether there is potentiation at clinically relevant concentrations. Information about the effects of Intravenous anesthetics with different behavioral profiles on specific ligand-gated ion channels may lead to hypotheses as to which ion channel effect produces a specific anesthetic behavior. Methods: A heteromeric nAChR composed of alpha 4 and beta 4 subunits was expressed heterologously in Xenopus laevis oocytes. Using the two-electrode voltage clamp technique, peak ACh-gated current was measured before and during application of ketamine, etomidate, or thiopental. The response to GABA of alpha 1 beta 2 gamma 2s GABA(A) receptors expressed in human embryonic kidney cells and Xenopus oocytes was compared with and without coapplication of ketamine from 1 mu M to 10 mM. Results: Ketamine caused potent, concentration-dependent inhibition of the alpha 4 alpha 4 nAChR current with an IC50 of 0.24 mu M. The inhibition by ketamine was use-dependent; the antagonist was more effective when the channel had been opened by agonist, Ketamine did not modulate the alpha 1 beta 2 gamma 2s GABA(A) receptor response in the clinically relevant concentration range. Thiopental caused 27% inhibition of ACh response at its clinical EC50. Etomidate did not modulate the alpha 4 beta 4 nAChR response in the clinically relevant concentration range, although there was inhibition at very high concentrations. Conclusions: The alpha 4 beta 4 nAChR, which is predominantly found in the central nervous system (CNS), is differentially affected by clinically relevant concentrations of Intravenous anesthetics. Ketamine, commonly known to be an inhibitor at the N-methyl-D-aspartate receptor, is also a potent inhibitor at a central nAChR. It has little effect on a common CNS GABA(A) receptor in a clinically relevant concentration range. Interaction between ketamine and specific subtypes of nAChRs In the CNS may result in anesthetic behaviors such as Inattention to surgical stimulus and In analgesia. Thiopental causes minor inhibition at the alpha 4 beta 4 nAChR. Modulation of the alpha 4 beta 4 nAChR by etomidate Is unlikely to be important In anesthesia practice based on the insensitivity of this receptor to clinically used concentrations.