This observation was supported by the fact that blockade of CRE-mediated gene expression (with ICER, an inhibitory CREB family member) increased NMDA-induced cell death, indicating click here that differential CREB activation contributes to CTD subtype-dependent regulation of excitotoxicity. What makes the two CTDs different? The answer appears to rely, in part, on enhanced coupling of CTD2B to the PSD-95/nNOS signaling cassette. It is known that nitric oxide (NO) is a key regulator of CREB phosphorylation. NO is produced when NMDAR-dependent

Ca2+ influx activates nNOS via PSD-95 association with GluN2 subunits. In additional experiments, Martel et al. (2012) found that GluN2B+/+ neurons coupled more strongly to NMDA-induced NO production and concluded that stronger CTD2B coupling to PSD-95, NO production, and nNOS-dependent CREB inactivation leads to enhanced vulnerability to excitotoxic insults. Finally, the basis for the stronger association of PSD-95 with GluN2BWT compared to GluN2B2A(CTR) was explored. An internal region of the CTD2B (1086–1157), when deleted, resulted in a decrease in PSD-95 association, Veliparib whereas overexpression of this region led to reduced NMDA-induced cell death. This region thus could be implicated in NMDAR signaling

leading to cell death. The idea that GluN2A and GluN2B subunits play different roles in diverse processes such as synaptic plasticity, intracellular signaling, and excitotoxicity has often been entertained. In the case of synaptic plasticity, experimental evidence is not conclusive, and it appears that both subunits are necessary (Müller et al., 2009). However, there is evidence PAK6 that GluN2A and GluN2B subunits affect α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking in opposite ways, with GluN2A promoting and GluN2B inhibiting surface expression of GluA1 subunits. In the realm of excitotoxicity, it was previously demonstrated that activation

of GluN2B-containing NMDA receptors, at either synaptic or extrasynaptic sites, leads to excitotoxicity, whereas activation of either synaptic or extrasynaptic GluN2A-contaning NMDARs promotes neuronal survival and is neuroprotective (Liu et al., 2007). In this study, administration of glycine alone or in the presence of a GluN2B antagonist attenuated ischemic brain damage. Understanding the mechanisms of NMDAR-mediated excitotoxicity is paramount to the development of better neuroprotective tools in acute and chronic conditions. While great strides had been made, many of them by Hardingham’s group, the intimate mechanisms of excitotoxicity had been missing. Although the increased presence of GluN2B subunits in extrasynaptic locations is still a matter of debate, the role of these subunits in NMDAR-mediated toxicity is well supported by experimental evidence.