Differential roles of GluN2A- and GluN2B-containing NMDA receptors in neuronal survival and death

Abstract

Glutamate-induced neurotoxicity is the primary molecular mechanism that induces neuronal death in a variety of pathologies in central nervous system (CNS). Toxicity signals are relayed from extracellular space to the cytoplasm by N-methyl-D-aspartate receptors (NMDARs) and regulate a variety of survival and death signaling. Differential subunit combinations of NMDARs confer neuroprotection or trigger neuronal death pathways depending on the subunit arrangements of NMDARs and its localization on the cell membrane. It is well-known that GluN2B-contaning NMDARs (GluN2BRs) preferentially link to signaling cascades involved in CNS injury promoting neuronal death and neurodegeneration. Conversely, less well-known mechanisms of neuronal survival signaling are associated with GluN2A-comtaining NMDARs (GluN2AR)-dependent signal pathways. This review will discuss the most recent signaling cascades associated with GluN2ARs and GluN2BRs.

Keywords: GluN2A; GluN2B; NMDA receptor; neuronal death; neuronal survival.

Figure 1

GluN2AR- and GluN2BR-interacting signaling in neuronal survival and death. 1) GluN2AR-PTEN-TDP-43: Activation of GluN2AR confers neuroprotection through downregulation of nuclear PTEN and enhancing function of TDP-43. 2) DJ-1-PTEN-PINK1-GluN2AR: DJ-1 negatively regulates PTEN function inducing neuroprotection by increasing PINK1 expression in the cytoplasm. PINK1 can positively regulate both GluN2AR activity and the Akt pathway to promote cell survival. 3) DJ-1-PTEN-GluN2BR: DJ-1 negatively regulates PTEN function to play a role by increasing GluN2BR activity. 4) GluN2BR-PINK1-Akt: GluN2BR activation can suppress function of PINK1 and the neuroprotective Akt pathway.