Pentobarbital differentially modulates α1β3δ and α1β3γ2L GABAA receptor currents
Pentobarbital differentially modulates α1β3δ and α1β3γ2L GABAA receptor currents
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DOI：
10.1124/mol.104.002543
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发表时间：
2004-10-01
影响因子：
3.6
通讯作者：
Macdonald, RL
中科院分区：
文献类型：
--
作者：
Feng, HJ;Bianchi, MT;Macdonald, RL
GABA（A）受体受多种化合物调节，包括神经类固醇和巴比妥酸盐。虽然巴比妥类药物对被认为主导阶段性（突触）GABA能抑制的α-GABA亚型的影响已被广泛研究，但戊巴比妥对被认为介导紧张性（突触外或突触周）抑制的α-GABA（A）受体动力学特性的影响尚不清楚。使用超快药物输送和单通道记录技术，我们证明了异构体特异性戊巴比妥调制低效率，最低限度地脱敏α 1 β 3 δ电流和高效率，迅速脱敏α 1 β 3 γ 2L电流。具体而言，饱和浓度的GABA，戊巴比妥大大增强峰值α 1 β 3 δ受体电流，但未能增强峰值α 1 β 3 γ 2L受体电流。此外，戊巴比妥对饱和GABA诱发的α 1 β 3 δ（增加）和α 1 β 3 γ 2L（减少）受体电流的脱敏作用相反。戊巴比妥增加稳态α 1 β 3 δ受体单通道开放时间主要是通过引入一个较长的开放状态，而对于α 1 β 3 γ 2L受体通道，戊巴比妥增加平均开放时间通过增加最长开放状态的比例和持续时间。数据支持以前的建议，GABA可能是一个部分激动剂在alphabetadelta亚型，这可能使他们特别敏感的变构调制。α 1 β 3 δ受体门控效应的显著增加表明，alphabetadelta亚型和由此推断的抑制的强直形式可能是巴比妥类药物的重要靶点。
GABA(A) receptors are modulated by a variety of compounds, including the neurosteroids and barbiturates. Although the effects of barbiturates on alphabetagamma isoforms, thought to dominate phasic ( synaptic) GABAergic inhibition, have been extensively studied, the effects of pentobarbital on kinetic properties of alphabetadelta GABA(A) receptors, thought to mediate tonic (extra- or perisynaptic) inhibition, are unknown. Using ultrafast drug delivery and single channel recording techniques, we demonstrate isoform-specific pentobarbital modulation of low-efficacy, minimally desensitizing alpha1beta3delta currents and high-efficacy, rapidly desensitizing alpha1beta3gamma2L currents. Specifically, with saturating concentrations of GABA, pentobarbital substantially potentiated peak alpha1beta3delta receptor currents but failed to potentiate peak alpha1beta3gamma2L receptor currents. Also, pentobarbital had opposite effects on the desensitization of alpha1beta3delta ( increased) and alpha1beta3gamma2L ( decreased) receptor currents evoked by saturating GABA. Pentobarbital increased steady-state alpha1beta3delta receptor single channel open duration primarily by introducing a longer duration open state, whereas for alpha1beta3gamma2L receptor channels, pentobarbital increased mean open duration by increasing the proportion and duration of the longest open state. The data support previous suggestions that GABA may be a partial agonist at alphabetadelta isoforms, which may render them particularly sensitive to allosteric modulation. The remarkable increase in gating efficacy of alpha1beta3delta receptors suggests that alphabetadelta isoforms, and by inference tonic forms of inhibition, may be important targets for barbiturates.