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Anesth Analg 2004;98:1297-1304
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000111108.78745.AD

ANESTHETIC PHARMACOLOGY

The Effects of Isoflurane on Desensitized Wild-Type and {alpha}1(S270H) {gamma}-Aminobutyric Acid Type A Receptors

Adam C. Hall, PhD*, Kathleen C. Rowan, MA*, Renna J. N. Stevens*, Jill C. Kelley{dagger}, and Neil L. Harrison, PhD{dagger} Section Editor

*Department of Biological Sciences, Neuroscience Program, Smith College, Northampton, Massachusetts, and the {dagger}Department of Anesthesiology, Weill Medical College, Cornell University, New York, New York

Address correspondence and reprint requests to Adam C. Hall, PhD, Department of Biological Sciences, Clark Science Center, Smith College, Northampton, MA 01063. Address email to ahall{at}science.smith.edu

{gamma}-aminobutyric acid type A receptors (GABAA-R) mediate synaptic inhibition and meet many pharmacological criteria required of important general anesthetic targets. During synaptic transmission GABA release is sufficient to saturate, maximally activate, and transiently desensitize postsynaptic GABAA-Rs. The resulting inhibitory postsynaptic currents (IPSCs) are prolonged by volatile anesthetics like isoflurane. We investigated the effects of isoflurane on maximally activated and desensitized GABAA-R currents expressed in Xenopus oocytes. Wild-type {alpha}1ß2 and {alpha}1ß2{gamma}2s receptors were exposed to 600 µM GABA until currents reached a steady-state desensitized level. At clinical concentrations (0.02–0.3 mM), isoflurane produced a dose-dependent enhancement of steady-state desensitized current in {alpha}1ß2 receptors, an effect that was less apparent in receptors including a {gamma}2s-subunit. When serine at position 270 is mutated to histidine ({alpha}1(S270H)) in the second transmembrane segment of the {alpha}1-subunit, the currents evoked by sub-saturating concentrations of GABA became less sensitive to isoflurane enhancement. In addition, isoflurane enhancements of desensitized currents were greatly attenuated by this mutation and were undetectable in {alpha}1(S270H)ß2{gamma}2s receptors. In conclusion, isoflurane enhancement of GABAA-R currents evoked by saturating concentrations of agonist is subunit-dependent. The effects of isoflurane on desensitized receptors may be partly responsible for the prolongation of IPSCs during anesthesia.

IMPLICATIONS: Isoflurane enhances desensitized {gamma}-aminobutyric acid type A receptor (GABAA-R) currents, an effect that is subunit-dependent and attenuated by a mutation in an {alpha}1-subunit pore residue of the GABAA-R. As GABA release at inhibitory synapses is typically saturating, isoflurane modulation of desensitized receptors may be partly responsible for prolongation of inhibitory postsynaptic currents during anesthesia.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press
Copyright © 2004 by the International Anesthesia Research Society.