Auto-modulation of neuroactive steroids on GABAA receptors: A novel pharmacological effect
Auto-modulation of neuroactive steroids on GABAA receptors: A novel pharmacological effect
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神经活性类固醇对 GABAA 受体的自动调节：一种新的药理作用
DOI：
10.1016/j.neuropharm.2006.09.009
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发表时间：
2007
影响因子：
4.7
通讯作者：
K. Wohlfarth
中科院分区：
文献类型：
--
作者：
F. Wegner;C. Rassler;C. Allgaier;K. Strecker;K. Wohlfarth
GABA A受体功能受多种重要药物调节，包括神经活性类固醇，其作用于变构调节位点并可在高浓度下直接激活GABA A受体通道。我们使用全细胞膜片钳记录和神经活性类固醇阿法沙龙的快速应用，以研究重复类固醇的影响。在所有研究的重组亚型（α1β3δ、α1β3γ2L、α6β3δ、α6β3γ2L）和分化的人NT 2神经元的GABA A受体上重复共同应用，阿法沙龙增强次最大GABA诱发电流显著增强。类似的增加电流振幅诱导重复应用高浓度的类固醇没有GABA。我们将这些可逆效应称为自动调节，因为类固醇的重复相互作用以时间和浓度依赖性方式增强了其自身在受体部位的药理学影响，而不影响GABA控制。与indiplon、THIP和戊巴比妥相比，使用神经类固醇5α-THDOC也测量了明显的自调节作用，表明类固醇特异性。蛋白激酶A抑制显著降低了α1β3γ2L、α6β3γ2L和α6β3δ亚型的阿法沙龙自身调节，同时增强了α1β3δ亚型的增强作用，表明受体亚基组成和磷酸化对类固醇作用具有重要影响。特别是在突触外GABA A受体部位，含有δ亚基的类固醇自身调节可能在增强GABA诱导电流的增强中起关键作用。
GABAAreceptor function is modulated by various important drugs including neuroactive steroids that act on allosteric modulatory sites and can directly activate GABAAreceptor channels at high concentrations. We used whole cell patch-clamp recordings and rapid applications of the neuroactive steroid alphaxalone to investigate repetitive steroid effects. Alphaxalone potentiation of submaximal GABA-evoked currents was enhanced significantly by repetitive coapplications at all investigated recombinant isoforms (α1β3δ, α1β3γ2L, α6β3δ, α6β3γ2L) and at GABAAreceptors of differentiated human NT2 neurons. A similar increase of current amplitudes was induced by repetitive applications of a high steroid concentration without GABA. We refer to these reversible effects as auto-modulation because repeated interactions of steroids enhanced their own pharmacological impact at the receptor sites in a time and concentration dependent manner without affecting GABA controls. Pronounced auto-modulatory actions were also measured using the neurosteroid 5α-THDOC in contrast to indiplon, THIP, and pentobarbital indicating a steroid specificity. Protein kinase A inhibition significantly reduced alphaxalone auto-modulation at α1β3γ2L, α6β3γ2L, and α6β3δ subtypes while it enhanced potentiation at α1β3δ isoforms suggesting a crucial influence of receptor subunit composition and phosphorylation for steroid actions. Especially at extrasynaptic GABAAreceptor sites containing the δ subunit steroid auto-modulation may have a critical role in enhancing potentiation of GABA-induced currents.
DOI：
10.1073/pnas.96.22.12905
发表时间：
1999-10-26
影响因子：
11.1
作者：
Mihalek, RM;Banerjee, PK;Homanics, GE
通讯作者：
Homanics, GE
DOI：
--
发表时间：
1989-03
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
D. Turner;R. Ransom;J. Yang;R. Olsen
通讯作者：
D. Turner;R. Ransom;J. Yang;R. Olsen
大鼠额叶皮层和脊髓中的 γ-氨基丁酸 A 受体复合物对类固醇调节表现出不同的反应。
影响因子：
3.6
作者：
Gee,KW;Lan,NC
通讯作者：
Lan,NC