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

NEUROPHARMACOLOGY

卷:62

Article

Castellino, Francis J.¹ 

[1] Univ Notre Dame, WM Keck Ctr Transgene Res, Notre Dame, IN 46556 USA

关键词: NMDA receptor subunits;    Conantokin inhibitors;    NMDAR inhibition;    Synaptic and extrasynaptic NMDA receptors;    Neuron signaling;    Actin organization;    Knockout mice;   

DOI  :  10.1016/j.neuropharm.2012.01.018

来源: Elsevier

【 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(-/-) 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. (C) 2012 Elsevier Ltd. All rights reserved.

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