Neuron
Volume 85, Issue 6, 18 March 2015, Pages 1305-1318
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Article
Context-Dependent GluN2B-Selective Inhibitors of NMDA Receptor Function Are Neuroprotective with Minimal Side Effects

https://doi.org/10.1016/j.neuron.2015.02.008Get rights and content
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Highlights

  • pH-dependent binding of a GluN2B modulator to the GluN1/GluN2B ATD heterodimer

  • pH dependence renders a GluN2B modulator more potent at acidic pH during ischemia

  • pH-dependent GluN2B inhibitors are neuroprotective in vivo with reduced side effects

  • A novel dicarboxylate pH sensor establishes precedent for proton sensitive domains

Summary

Stroke remains a significant problem despite decades of work on neuroprotective strategies. NMDA receptor (NMDAR) antagonists are neuroprotective in preclinical models, but have been clinically unsuccessful, in part due to side effects. Here we describe a prototypical GluN2B-selective antagonist with an IC50 value that is 10-fold more potent at acidic pH 6.9 associated with ischemic tissue compared to pH 7.6, a value close to the pH in healthy brain tissue. This should maximize neuroprotection in ischemic tissue while minimizing on-target side effects associated with NMDAR blockade in noninjured brain regions. We have determined the mechanism underlying pH-dependent inhibition and demonstrate the utility of this approach in vivo. We also identify dicarboxylate dimers as a novel proton sensor in proteins. These results provide insight into the molecular basis of pH-dependent neuroprotective NMDAR block, which could be beneficial in a wide range of neurological insults associated with tissue acidification.

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