Wang X H, Zhu W J, Corsi L, Ikonomovic S, Paljug W R, Vicini S, Grayson D R
Center for Neuroscience Research, Allegheny University of the Health Sciences, Pittsburgh, Pennsylvania 15212, USA.
J Neurochem. 1998 Aug;71(2):693-704. doi: 10.1046/j.1471-4159.1998.71020693.x.
We investigated the effect of chronically blocking NMDA receptor stimulation to examine changes in GABA(A) receptor expression and pharmacology in cerebellar granule cells at different stages of maturation. We have previously shown that NMDA-selective glutamate receptor stimulation alters GABA(A) receptor pharmacology in cerebellar granule neurons in vitro by altering the levels of selective subunits. When NMDA receptor stimulation is blocked with MK-801 during the first week in vitro, a decrease in the alpha1, gamma2S, and gamma2L receptor subunit mRNAs occurred. When present only during the second week, changes were limited to the alpha1 and gamma2L mRNAs. Finally, if MK-801 was present during the first week and removed during the second week, these changes reversed. Whole-cell voltage-clamp recordings showed that treatment with MK-801 during either the first or second week increased the EC50 of the receptors for GABA and attenuated the potentiation mediated by flunitrazepam. Last, these properties were reversed if MK-801 was removed after the first week in vitro. Our results suggest that MK-801 reversibly inhibits GABA(A) receptor maturation by modulating receptor subunit expression and that the altered pharmacological responses appear to be dominated by changes in the levels of allosteric modulation mediated by the gamma2 receptor subunit.
我们研究了长期阻断N-甲基-D-天冬氨酸（NMDA）受体刺激对不同成熟阶段小脑颗粒细胞中γ-氨基丁酸A（GABA(A)）受体表达和药理学变化的影响。我们之前已经表明，NMDA选择性谷氨酸受体刺激通过改变选择性亚基的水平，在体外改变小脑颗粒神经元中的GABA(A)受体药理学。当在体外第一周用MK-801阻断NMDA受体刺激时，α1、γ2S和γ2L受体亚基的mRNA水平下降。当仅在第二周存在时，变化仅限于α1和γ2L的mRNA。最后，如果MK-801在第一周存在并在第二周去除，这些变化会逆转。全细胞膜片钳记录显示，在第一周或第二周用MK-801处理会增加受体对GABA的半数有效浓度（EC50），并减弱氟硝西泮介导的增强作用。最后，如果在体外第一周后去除MK-801，这些特性会逆转。我们的结果表明，MK-801通过调节受体亚基表达可逆地抑制GABA(A)受体成熟，并且改变的药理学反应似乎主要由γ2受体亚基介导的变构调节水平的变化所主导。
