Phosphorylation influences neurosteroid modulation of synaptic GABAA receptors in rat CA1 and dentate gyrus neurones
Phosphorylation influences neurosteroid modulation of synaptic GABAA receptors in rat CA1 and dentate gyrus neurones
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DOI：
10.1016/s0028-3908(03)00251-x
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发表时间：
2003-11-01
影响因子：
4.7
通讯作者：
Lambert, JJ
中科院分区：
文献类型：
--
作者：
Harney, SC;Frenguelli, BG;Lambert, JJ
神经类固醇 5beta-pregnan-3alpha-ol-20-one (5beta3alpha) 是 GABA(A) 受体的有效、内源性正变构调节剂。相对较低浓度的 5beta3α (10-100 nM)，被认为是生理上发生的，导致从海马 CA1 锥体神经症患者记录的 GABA 介导的微型抑制性突触后电流 (mIPSC) 的衰减出现浓度依赖性减慢。然而，需要更高浓度的这种神经类固醇（大于或等于300 nM）才能类似地影响齿状颗粒细胞mIPSC。相比之下，变构调节剂戊巴比妥和氟硝西泮在延长两种神经元类型的 mIPSC 方面效果相同。因此，神经类固醇选择性地区分这些海马神经症的突触 GABA(A) 受体。抑制蛋白激酶 A 或 C 会大大降低 CA1 突触 GABA(A) 受体对 5beta3α 的敏感性，但不会降低戊巴比妥。而刺激 PKC 对类固醇敏感性没有影响。然而，在齿状回颗粒细胞中，PKC 的激活使 mIPSC 对先前无效浓度的 5β3α 敏感。总的来说，这些结果表明神经类固醇的生理水平的 GABA 调节作用不会在整个中枢神经系统中均匀地经历。或者甚至在同一大脑区域（例如海马体）内，但具有神经元特异性，并且取决于 GABA(A) 受体或相关蛋白的磷酸化状态。 (C) 2003 Elsevier Ltd. 保留所有权利。
The neurosteroid 5beta-pregnan-3alpha-ol-20-one (5beta3alpha) is a potent, endogenous, positive allosteric modulator of the GABA(A) receptor. Relatively low concentrations of 5beta3alpha (10-100 nM), thought to occur physiologically, caused a concentration-dependent slowing of the decay of GABA-mediated miniature inhibitory postsynaptic currents (mIPSCs) recorded from hippocampal CA1 pyramidal neurotics. However, much greater concentrations of this neurosteroid (greater than or equal to300 nM) were required to similarly influence dentate granule cell mIPSCs. By contrast, the allosteric modulators pentobarbitone and flunitrazepam were equi-effective in prolonging mIPSCs in both neuronal types. Hence, the neurosteroid selectively differentiates between the synaptic GABA(A) receptors of these hippocampal neurotics. Inhibition of either protein kinase A, or C, greatly reduced the sensitivity of CA1 synaptic GABA(A), receptors to 5beta3alpha, but not pentobarbitone. whereas stimulation of PKC had no effect on steroid sensitivity. However, in dentate gyrus granule cells, activation of PKC made mIPSCs sensitive to a previously ineffective concentration of 5beta3alpha. Collectively, these results Suggest that the GABA-modulatory effects of physiological levels of the neurosteroid will not be uniformly experienced throughout the central nervous system. or even,within the same brain region such as the hippocampus, but will be neurone-specific and will be dependent on the phosphorylation status of the GABA(A) receptor, or associated proteins. (C) 2003 Elsevier Ltd. All rights reserved.