The general anesthetic propofol slows deactivation and desensitization of GABAA receptors
The general anesthetic propofol slows deactivation and desensitization of GABAA receptors
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DOI：
10.1523/jneurosci.19-24-10635.1999
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发表时间：
1999-12-15
影响因子：
5.3
通讯作者：
Orser, BA
中科院分区：
文献类型：
--
作者：
Bai, DL;Pennefather, PS;Orser, BA
丙泊酚（2，6-二异丙基苯酚）对GABA（A）受体功能有多种作用，这些作用共同增强GABA诱发电流。为了了解丙泊酚如何影响抑制性IPSC，我们研究了丙泊酚对短暂应用饱和浓度GABA（1-30 mM）的反应的影响。使用快速灌注系统将GABA施加到从海马神经元切除的有核贴片。在该制剂中，丙泊酚（10 μ M）没有可检测到的激动剂作用，但减慢衰减，增加电荷转移（62%），并增强GABA的短脉冲（3毫秒）诱导的电流的峰值幅度（8%）。GABA的较长脉冲（500毫秒）诱导的反应用快（τ（f）= 1.5-4.5毫秒）和慢（τ（s）= 1-3秒）分量脱敏，并且在去除GABA后，指数地失活（τ（d）= 151毫秒）。异丙酚延长了这种失活（τ（d）= 255毫秒），并减少了快速和缓慢脱敏的发展。从快速脱敏中恢复，使用GABA的短暂脉冲对评估，抑制失活的时间过程，表明快速脱敏将GABA捕获在受体上。随着GABA（0.33 Hz）脉冲的重复应用，每个脉冲的电荷转移以指数方式下降（τ近似为15秒）至等于初始响应的40%的稳态值。尽管丙泊酚增加了每个脉冲的电荷转移，但下降的时间过程没有改变。这些实验数据进行了解释，使用计算机模拟和动力学模型，假设快速和缓慢的脱敏，以及从一个开放前的状态并行开发的通道开放。我们的研究结果表明，异丙酚稳定的双配体预开放状态，而不影响异构化速率常数和开放状态。此外，丙泊酚降低了激动剂解离和进入快速和缓慢脱敏状态的速率常数。从快速脱敏的恢复速率常数减慢，而从缓慢脱敏似乎是不变的。总之，丙泊酚对GABA（A）受体的作用增强了通道开放，特别是在促进脱敏的条件下。
Propofol (2,6-di-isopropylphenol) has multiple actions on GABA(A) receptor function that act in concert to potentiate GABA-evoked currents. To understand how propofol influences inhibitory IPSCs, we examined the effects of propofol on responses to brief applications of saturating concentrations of GABA (1-30 mM). GABA was applied using a fast perfusion system to nucleated patches excised from hippocampal neurons. In this preparation, propofol (10 mu M) had no detectable agonist effect but slowed the decay, increased the charge transfer (62%), and enhanced the peak amplitude (8%) of currents induced by brief pulses (3 msec) of GABA. Longer pulses (500 msec) of GABA induced responses that desensitized with fast (tau(f) = 1.5-4.5 msec) and slow (tau(s) = 1-3 sec) components and, after the removal of GABA, deactivated exponentially (tau(d) = 151 msec). Propofol prolonged this deactivation (tau(d) = 255 msec) and reduced the development of both fast and slow desensitization. Recovery from fast desensitization, assessed using pairs of brief pulses of GABA, paralleled the time course of deactivation, indicating that fast desensitization traps GABA on the receptor. With repetitive applications of pulses of GABA (0.33 Hz), the charge transfer per pulse declined exponentially (tau approximate to 15 sec) to a steady-state value equal to similar to 40% of the initial response. Despite the increased charge transfer per pulse with propofol, the time course of the decline was unchanged. These experimental data were interpreted using computer simulations and a kinetic model that assumed fast and slow desensitization, as well as channel opening developed in parallel from a pre-open state. Our results suggest that propofol stabilizes the doubly liganded pre-open state without affecting the isomerization rate constants to and from the open state. Also, the rate constants for agonist dissociation and entry into the fast and slow desensitization states were reduced by propofol. The recovery rate constant from fast desensitization was slowed, whereas that from slow desensitization appeared to be unchanged. Taken together, the effects of propofol on GABA(A) receptors enhance channel opening, particularly under conditions that promote desensitization.