Therapeutic Targets for Cerebral Ischemia Based on the Signaling Pathways of the GluN2B C Terminus

Abstract

Overactivation of the N-methyl-d-aspartate receptor (NMDAR) after cerebral ischemia is a crucial reason for neuron death. Although NMDAR antagonists have exhibited neuroprotective effects in animal models, it is disappointing that several severe side effects have occurred in patients. NMDAR is a heteromer containing 2 obligate N-methyl-D-aspartate receptor 1 (GluN1) subunits and a variety of GluN2 and GluN3 subunits. The GluN2 subunit, which contributes specifically to neuron death after stroke, has been studied extensively. An opposing action of the GluN2A and GluN2B subunits in mediating cell death and cell survival was observed.1,2 The results indicate that the GluN2A subunit produces prosurvival activity, whereas the GluN2B subunit leads to a prodeath signal. However, von Engelhardt et al3 found that the GluN2A subunit can also mediate NMDA-dependent toxicity in DIV21 cultures. This paradox may have resulted because the pharmacological approach used to study subunit composition was not flawless.4 In view of this limitation and according to the methods of molecular biology, Martel et al5 demonstrated that the C-terminal domains of GluN2B promote neuronal death more efficiently than those of GluN2A in cerebral ischemia.5 In short, NMDARs containing GluN2B are more lethal than those containing GluN2A. Prodeath signaling pathways mediated by neuronal nitric oxide synthase (nNOS), death-associated protein kinase 1 (DAPK1), phosphatase and tensin homolog located on chromosome 10 (PTEN), and calcium/calmodulin-dependent protein kinase II (CaMKII) have been linked to GluN2B activation. Therapeutic targets based on these signaling pathways of the GluN2B carboxyl terminus (C terminus) will be introduced in this review. ### GluN2B–nNOS Signaling Pathway The GluN2B–nNOS signaling pathway, which plays an important role in neuron death, is the most widely studied GluN2B pathway (Figure 1). Figure 1. The GluN2B–nNOS signaling pathway. Based on the PDZ domains, postsynaptic density-95 (PSD-95) assembles GluN2B and nNOS into a macromolecular complex. After …