Cyclothiazide potently inhibits γ-aminobutyric acid type A receptors in addition to enhancing glutamate responses
Cyclothiazide potently inhibits γ-aminobutyric acid type A receptors in addition to enhancing glutamate responses
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DOI：
10.1073/pnas.2133370100
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发表时间：
2003-10-28
影响因子：
11.1
通讯作者：
Chen, G
中科院分区：
文献类型：
--
作者：
Deng, LB;Chen, G
嗜电性谷氨酸和γ -氨基丁酸A型（GABA(A)）受体在大脑中介导关键的兴奋和抑制作用。环噻嗪（Cyclothiazide， CTZ）以其增强谷氨酸能传递的作用而闻名，被广泛用作α -氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）型谷氨酸受体脱敏的阻滞剂。在这里，我们报道了CTZ除了对AMPA受体的作用外，对GABA(a)受体也有强大但相反的作用。我们发现CTZ以剂量依赖的方式可逆地抑制诱发和自发抑制性突触后电流，以及GABA应用诱导的膜电流。单通道分析进一步表明，CTZ大大降低了GABA(A)受体通道的开放概率。这些结果表明，CTZ与谷氨酸和GABA(A)受体相互作用，并通过两种独立的机制改变大脑中的兴奋-抑制平衡。了解这种双重药物受体相互作用的分子机制可能有助于设计神经系统疾病的新疗法。
Ionotropic glutamate and gamma-aminobutyric acid type A (GABA(A)) receptors mediate critical excitatory and inhibitory actions in the brain. Cyclothiazide (CTZ) is well known for its effect of enhancing glutamatergic transmission and is widely used as a blocker for alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)type glutamate receptor desensitization. Here, we report that in addition to its action on AMPA receptors, CTZ also exerts a powerful but opposite effect on GABA(A) receptors. We found that CTZ reversibly inhibited both evoked and spontaneous inhibitory postsynaptic currents, as well as GABA application-induced membrane currents, in a dose-dependent manner. Single-channel analyses revealed further that CTZ greatly reduced the open probability of GABA(A) receptor channels. These results demonstrate that CTZ interacts with both glutamate and GABA(A) receptors and shifts the excitation-inhibition balance in the brain by two independent mechanisms. Understanding the molecular mechanism of this double-faceted drug-receptor interaction may help in designing new therapies for neurological diseases.