Bidirectional modulation of GABA-gated chloride channels by divalent cations: inhibition by Ca2+ and enhancement by Mg2+.
Bidirectional modulation of GABA-gated chloride channels by divalent cations: inhibition by Ca2+ and enhancement by Mg2+.
复制标题
二价阳离子对 GABA 门控氯通道的双向调节：Ca2+ 抑制，Mg2+ 增强。
DOI：
10.1046/j.1471-4159.1994.62030916.x
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发表时间：
1994
影响因子：
4.7
通讯作者：
Martin,D
中科院分区：
文献类型：
--
作者：
Schwartz,RD;Wagner,JP;Yu,X;Martin,D
本文研究了二价阳离子Ca ~（2+）、Sr ~（2+）、Ba ~（2+）、Mg ~（2+）、Mn ~（2+）和Cd ~（2+）对大鼠大脑皮层突触神经元γ-氨基丁酸A（GABAA）反应的影响。二价阳离子产生蝇蕈醇诱导的36 Cl −摄取的双向调节，与其渗透和阻断Ca 2+通道的能力一致。蝇蕈醇抑制神经元钙通道的顺序为Ca ~（2+）> Sr ~（2+）> Ba ~（2+）。蝇蕈醇增强神经元钙通道反应的能力顺序为Cd ~（2+）> Mn ~（2+）> Mg ~（2+），与阻断神经元钙通道的顺序相似。无论是Ca 2+，也不Mg 2+引起的GABA的积累在囊外空间由于增加GABA的释放或减少GABA的突触神经小体的再摄取。蝇蕈醇反应的抑制Ca 2+是最有可能通过细胞内的作用位点，因为额外的抑制可以在Ca 2+离子载体，A23187的存在下获得。这证实了几个物种的培养神经元的电生理学结果。相反，Cd 2+，Mn 2+和Mg 2+的影响可能是通过阻断Ca 2+通道或通过细胞内位点介导的，尽管这些研究的结果没有区分这两个位点。还研究了Zn 2+的影响，因为据报道这种二价阳离子对GABAA反应具有广泛的不同影响。与其他研究相比，我们证明，锌离子抑制GABAA反应在成人神经元制备。Zn 2+对蝇蕈醇反应产生浓度依赖性抑制（限于40%），EC 50为60 μM。Zn 2+对蝇蕈醇诱导的38 Cl −摄取的抑制是非竞争性的。在Mg ~（2+）存在下，Zn ~（2+）的作用以竞争或变构方式减弱。对Zn 2+敏感的GABAA受体的部分可能反映了大脑皮层中的特定亚基组成，如先前在几种表达系统中观察到的重组GABAA受体。Ca ~（2+）和其它二价阳离子对GABA_A受体功能的调节可能在与病理状态如癫痫发作活动和脑缺血相关的神经元兴奋性的发展和/或衰减中起重要作用。
The effects of the divalent cations Ca2+, Sr2+, Ba2+, Mg2+, Mn2+, and Cd2+were studied on γ‐aminobutyric acidA(GABAA) responses in rat cerebral cortical synaptoneurosomes. The divalent cations produced bidirectional modulation of muscimol‐induced36Cl−uptake consistent with their ability to permeate and block Ca2+channels. The order of potency for inhibition of muscimol responses was Ca2+> Sr2+> Ba2+, similar to the order for permeation of Ca2+channels in neurons. The order of potency for enhancement of muscimol responses was Cd2+> Mn2+> Mg2+, similar to the order for blockade of Ca2+channels in neurons. Neither Ca2+nor Mg2+caused accumulation of GABA in the extravesicular space due to increased GABA release or decreased reuptake of GABA by the synaptoneurosomes. The inhibition of muscimol responses by Ca2+was most likely via an intracellular site of action because additional inhibition could be obtained in the presence of the Ca2+ionophore, A23187. This confirms electrophysiologic findings in cultured neurons from several species. In contrast, the effects of Cd2+, Mn2+, and Mg2+may be mediated via blockade of Ca2+channels or by intracellular sites, although the results of these studies do not distinguish between the two loci. The effects of Zn2+were also studied, because this divalent cation is reported to have widely divergent effects on GABAAresponses. In contrast to other studies, we demonstrate that Zn2+inhibits GABAAresponses in an adult neuronal preparation. Zn2+produced a concentration‐dependent inhibition (limited to 40%) of muscimol responses with an EC50of 60 μM. The inhibition of muscimol‐induced38Cl−uptake by Zn2+was noncompetitive. The effect of Zn2+was reduced in the presence of Mg2+in a competitive or allosteric manner. The portion of GABAAreceptors sensitive to Zn2+may reflect a specific subunit composition in cerebral cortex as previously observed for recombinant GABAAreceptors in several expression systems. The modulation of GABAAreceptor function by Ca2+and other divalent cations may play an important role in the development and/or attenuation of neuronal excitability associated with pathologic conditions such as seizure activity and cerebral ischemia.