Opposing action of conantokin-G on synaptically and extrasynaptically-activated NMDA receptors

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• 作者：Rashna Balsara ; Neill Li ; Danielle Weber-Adrian ; Louxiu Huang ; Francis J. Castellino ; ^{fjc3743@sbcglobal.net} ; ^{fcastell@nd.edu}
• 关键词：NMDA receptor subunits ; Conantokin inhibitors ; NMDAR inhibition ; Synaptic and extrasynaptic NMDA receptors ; Neuron signaling ; Actin organization ; Knockout mice
• 刊名：Neuropharmacology
• 出版年：2012
• 期刊代码：33_00283908
• 类别：pha
• 出版时间：June, 2012
• 卷：62
• 期：7
• 页码：2227-2238
• 文件大小：1293 K

摘要

Synaptic and extrasynaptic activation of the N-methyl-d-aspartate receptor (NMDAR) has distinct consequences on cell signaling and neuronal survival. Since conantokin (con)-G antagonism is NR2B-selective, which is the key subunit involved in extrasynaptic activation of the receptor, its ability to specifically elicit distinct signaling outcomes in neurons with synaptically or extrasynaptically-activated NMDARs was evaluated. Inhibition of Ca²⁺ influx through extrasynaptic NMDAR ion channels was neuroprotective, as it effectively enhanced levels of activated extracellular signal-regulated kinase 1/2 (ERK1/2), activated cAMP response element binding protein (CREB), enhanced mitochondrial viability, and attenuated the actin disorganization observed by extrasynaptic activation of NMDARs. Conversely, the pro-signaling pathways stimulated by synaptically-induced Ca²⁺ influx were abolished by con-G. Furthermore, subunit non-selective con-T was unable to successfully redress the impairments in neurons caused by extrasynaptically-activated NMDARs, thus indicating that NR2B-specific antagonists are beneficial for neuron survival. Neurons ablated for the NR2B subunit showed weak synaptic Ca²⁺ influx, reduced sensitivity to MK-801 blockage, and diminished extrasynaptic current compared to WT and NR2A^{鈭?鈭?/sup> neurons. This indicates that the NR2B subunit is an integral component of both synaptic and extrasynaptic NMDAR channels. Altogether, these data suggest that con-G specifically targets the NR2B subunit in the synaptic and extrasynaptic locations, resulting in the opposing action of con-G on differentially activated pools of NMDARs.}