Dual actions of enflurane on postsynaptic currents abolished by the γ-aminobutyric acid type A receptor β 3(N265M) point mutation

Abstract

BACKGROUND: At concentrations close to 1 minimum alveolar concentration (MAC)-immobility, volatile anesthetics display blocking and prolonging effects on γ-aminobutyric acid type A receptor-mediated postsynaptic currents. It has been proposed that distinct molecular mechanisms underlie these dual actions. The authors investigated whether the blocking or the prolonging effect of enflurane is altered by a point mutation (N265M) in the β3 subunit of the γ-aminobutyric acid type A receptor. Furthermore, the role of the β3 subunit in producing the depressant actions of enflurane on neocortical neurons was elucidated. METHODS: Spontaneous inhibitory postsynaptic currents were sampled from neocortical neurons in cultured slices derived from wild-type and β3(N265M) mutant mice. The effects of 0.3 and 0.6 mm enflurane on decay kinetics, peak amplitude, and charge transfer were quantified. Furthermore, the impact of enflurane-induced changes in spontaneous action potential firing was evaluated by extracellular recordings in slices from wild-type and mutant mice. RESULTS: In slices derived from wild-type mice, enflurane prolonged inhibitory postsynaptic current decays and decreased peak amplitudes. Both effects were almost absent in slices from β3(N265M) mutant mice. At clinically relevant concentrations between MAC-awake and MAC-immobility, the anesthetic was less effective in depressing spontaneous action potential firing in slices from β3(N265M) mutant mice compared with wild-type mice. CONCLUSIONL At concentrations between MAC-awake and MAC-immobility, β3-containing γ-aminobutyric acid type A receptors contribute to the depressant actions of enflurane in the neocortex. The β3(N265M) mutation affects both the prolonging and blocking effects of enflurane on γ-aminobutyric acid type A receptor-mediated inhibitory postsynaptic currents in neocortical neurons. © 2006 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc.