Drexler Berthold, Jurd Rachel, Rudolph Uwe, Antkowiak Bernd
Department of Anesthesiology, Experimental Anesthesiology Section, University of Tuebingen, Germany.
Anesthesiology. 2006 Aug;105(2):297-304. doi: 10.1097/00000542-200608000-00012.
At concentrations close to 1 minimum alveolar concentration (MAC)-immobility, volatile anesthetics display blocking and prolonging effects on gamma-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 beta3 subunit of the gamma-aminobutyric acid type A receptor. Furthermore, the role of the beta3 subunit in producing the depressant actions of enflurane on neocortical neurons was elucidated.
Spontaneous inhibitory postsynaptic currents were sampled from neocortical neurons in cultured slices derived from wild-type and beta3(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.
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 beta3(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 beta3(N265M) mutant mice compared with wild-type mice.
At concentrations between MAC-awake and MAC-immobility, beta3-containing gamma-aminobutyric acid type A receptors contribute to the depressant actions of enflurane in the neocortex. The beta3(N265M) mutation affects both the prolonging and blocking effects of enflurane on gamma-aminobutyric acid type A receptor-mediated inhibitory postsynaptic currents in neocortical neurons.
在接近1个最低肺泡有效浓度（MAC）-制动浓度时，挥发性麻醉药对γ-氨基丁酸A型（GABA A）受体介导的突触后电流具有阻断和延长作用。有人提出，这些双重作用有不同的分子机制。作者研究了GABA A受体β3亚基中的一个点突变（N265M）是否会改变恩氟烷的阻断或延长作用。此外，还阐明了β3亚基在恩氟烷对新皮质神经元产生抑制作用中的作用。
从野生型和β3（N265M）突变型小鼠的培养切片中的新皮质神经元采集自发性抑制性突触后电流。对0.3和0.6 mM恩氟烷对衰减动力学、峰值幅度和电荷转移的影响进行了量化。此外，通过对野生型和突变型小鼠切片的细胞外记录，评估了恩氟烷诱导的自发性动作电位发放变化的影响。
在野生型小鼠的切片中，恩氟烷延长了抑制性突触后电流的衰减并降低了峰值幅度。在β３（N265M）突变型小鼠的切片中，这两种作用几乎都不存在。在MAC-清醒和MAC-制动之间的临床相关浓度下，与野生型小鼠相比，麻醉药对β3（N265M）突变型小鼠切片中自发性动作电位发放的抑制作用较弱。
在MAC-清醒和MAC-制动之间浓度时，含β3的GABA A受体有助于恩氟烷在新皮质中的抑制作用。β3（N265M）突变影响恩氟烷对新皮质神经元中GABA A受体介导的抑制性突触后电流的延长和阻断作用。
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