Fig. 3

Distinctive Pro- and anti-survival mechanisms downstream from activation of synaptic and extrasynaptic NMDARs. This simplified graph illustrates a few main signaling pathways associated with the activation of synaptic and extrasynaptic NMDA receptors, respectively. Of note that although additional genes not mentioned in the text are shown in the graph, not all related signals can be included in the graph. For example, chronic stress of neuronal hyperactivity and Ca²⁺ elevations induce recurrent inflammation that is not shown here. In general, activation of sNMDARs leads to pro-survival effects beneficial for neuronal viability and synaptic plasticity, while activation of eNMDARs causes detrimental consequences associated with acute and chronic excitotoxicity. It is worth mentioning, however, that many signaling genes such as CaMK and MAPK kinases can play opposite actions most likely in subtype-dependent manners. In the pro-survival mechanism, the Wnt regulation of the expression of CaMKIV is an upstream protective signaling in neurodegenerative conditions [342]. Cyclic-AMP response element binding protein (CREB) plays a key function in medicating sNMDAR activation and expressions of pro-survival genes such as BDNF, MAPK, and Akt. CREB phosphorylation is mediated acutely by CaMKIV while long-term regulation may be controlled upstream by ERK1/2 [343, 344]. Activation of CREB via CaMKIV phosphorylation of CREB binding protein (CBP) requires translocation of transducer of regulated CREB activity (TORC) which is downstream of Ca²⁺ signaling from sNMDAR activation. Jacob and the synapto-nuclear trafficking is a relatively new mechanism linking downstream signaling of sNMDARs. Caldendrin binds to Jacob’s nuclear localization signal in a Ca²⁺-dependent manner [194, 195]. In contrast to these CREB-activating signals of sNMDARs, eNMDARs suppress CREB activity via the inactivation of the Ras-ERK1/2 pathway and the nuclear translocation of Jacob, which promotes CREB dephosphorylation. Calcineurin-dependent dephosphorylation of TORC and subsequent CREB activation is also downstream of sNMDAR transmission [345]. Activation of sNMDARs suppresses apoptotic cascades via suppression of the BH3-only domain gene Puma and p53, thereby limiting cytochrome c release. Downstream effectors of apoptosis including Apaf1, Caspase 3, and Caspase 9 are also suppressed [346, 347]. Contrary to these pro-survival pathways, pro-death pathways are mediated by downstream activities of eNMDARs [189, 348]. Interactions between the pro-survival and pro-death pathways may occur so that the suppression of CREB activity may result from inactivating the ERK1/2 pathway [79, 195]. Another shared pathway between synaptic and extrasynaptic NMDARs is the FOXO pathway. FOXO activity is suppressed by PI3K downstream of sNMDARs while activation of eNMDARs enhances FOXO nuclear import and the consequent transcription of FOXO3α, Bim, and Fas which lead to cell death via multiple mechanisms including excitotoxicity [205, 349]. Synaptic NMDAR activity enhances the transcription of PGC-1α, while excessive expression and activity of eNMDARs suppress CREB-dependent PGC-1α transcription [350]. In general, CaMKII is downstream of eNMDAR activity and acts as a carrier of Ca²⁺-regulated protease calpain to promote apoptotic cell death [351]. Moreover, Ca²⁺ dyshomeostasis resulting from NMDAR subunit composition such as GluN2B and GluN3A expression changes and its interaction with intracellular Ca²⁺ reservoirs in the ER and mitochondria play an important role in the maintenance of cellular bioenergetics, glucose metabolism, and normal mitophagy [352]. Ca²⁺ dyshomeostasis is thus a major trigger of the generation of ROS and increased apoptosis via the imbalance of mitochondria-initiated apoptotic genes including tBid, Bax/Bcl2, Bak/BclxL, Bad, Apaf1, cytochrome c, and caspases [353, 354]. The NMDAR-TRPM interaction is a novel cell death mechanism downstream to NMDAR and TRPM activation, which stimulates the formation of the NMDAR/TRPM complex in the extrasynaptic location. Excitotoxicity is then triggered by the complex in a “Ca²⁺-independent” fashion, mediated by mitochondrial dysfunction, reduced activation of ERK1/2, shut-off of the transcription factor CRAB, and cell death [229]