GluN2A and GluN2B N-Methyl-D-Aspartate Receptor (NMDARs) Subunits: Their Roles and Therapeutic Antagonists in Neurological Diseases

Abstract

N-methyl-D-aspartate receptors (NMDARs) are ion channels that respond to the neurotransmitter glutamate, playing a crucial role in the permeability of calcium ions and excitatory neurotransmission in the central nervous system (CNS). Composed of various subunits, NMDARs are predominantly formed by two obligatory GluN1 subunits (with eight splice variants) along with regulatory subunits GluN2 (GluN2A-2D) and GluN3 (GluN3A-B). They are widely distributed throughout the CNS and are involved in essential functions such as synaptic transmission, learning, memory, plasticity, and excitotoxicity. The presence of GluN2A and GluN2B subunits is particularly important for cognitive processes and has been strongly implicated in neurodegenerative diseases like Parkinson’s disease and Alzheimer’s disease. Understanding the roles of GluN2A and GluN2B NMDARs in neuropathologies provides valuable insights into the underlying causes and complexities of major nervous system disorders. This knowledge is vital for the development of selective antagonists targeting GluN2A and GluN2B subunits using pharmacological and molecular methods. Such antagonists represent a promising class of NMDA receptor inhibitors that have the potential to be developed into neuroprotective drugs with optimal therapeutic profiles.

Gypenoside XVII Reduces Synaptic Glutamate Release and Protects against Excitotoxic Injury in Rats

“…NMDA receptors consist of two obligatory GluN1 subunits and various combinations of the same or different GluN2 (GluN2A-2D) and GluN3 subunits [59]. Among the NMDA receptor subunits, the GluN2 subunit mainly determines NMDA receptor function, particularly the GluN2A and GluN2B subunits, which are highly expressed in excitatory neurons and have differential roles in mediating excitotoxic neuronal death [60]. For example, the activation of GluN2A-containing NMDA receptors promotes neuronal survival and exerts a neuroprotective effect, whereas the activation of GluN2B-containing receptors causes an excessive increase in intracellular Ca 2+ , leading to neuronal death [61].…”

Abstinence and Fear Experienced during This Period Produce Distinct Cortical and Hippocampal Adaptations in Alcohol-Dependent Rats

“…For example, the blockade of GluN receptors prior to training disrupts the consolidation of fear memories [99], and similarly, the genetic deletion of hippocampal GluNs disrupts TFC [97]. The GluN2A and GluN2B subunits mark the principal GluN subtypes, and the ratio of GluN2A/2B determines the qualitative and functional properties of neurons and affects the expression of fear memories [63,98,[100][101][102]. Our findings demonstrate that TFC enhances the GluN2A/2B ratio under control and CIE conditions in the mPFC and reduces the GluN2A/2B ratio under these conditions in the DG.…”

Origanum majorana L. polyphenols: in vivo antiepileptic effect, in silico evaluation of their bioavailability, and interaction with the NMDA receptor

“…The PDB format of the human GluN1-GluN2A (PDB: 7EU7) and GluN1-GluN2B (PDB: 7EU8) NMDA receptor crystal structures in three dimensions were acquired from the protein data bank (Zhang et al, 2021;Ladagu et al, 2023). The structures were refined and prepared using the Protein Preparation Wizard in the Schrödinger-Maestro program (v11.5).…”