The Functional and Molecular Properties, Physiological Functions, and Pathophysiological Roles of GluN2A in the Central Nervous System

Abstract

The NMDA receptor, which is heavily involved in several human brain diseases, is a heteromeric ligand-gated ion channel that interacts with multiple intracellular proteins through the C-termini of different subunits. GluN2A and GluN2B are the two primary types of GluN2 subunits in the forebrain. During the developmental period, there is a switch from GluN2B- to GluN2A-containing NMDA receptors in synapses. In the adult brain, GluN2A exists at synaptic sites more abundantly than GluN2B. GluN2A plays important roles not only in synaptic plasticity but also in mediating physiological functions, such as learning and memory. GluN2A has also been involved in many common human diseases, such as cerebral ischemia, seizure disorder, Alzheimer's disease, and systemic lupus erythematosus. The following review investigates the functional and molecular properties, physiological functions, and pathophysiological roles of the GluN2A subunit.

Synaptic GluN2A-Containing NMDA Receptors: From Physiology to Pathological Synaptic Plasticity

“…In this regard, GluN2A subunit has been intensively studied, as GluN2A-containing NMDAR has particular channel properties that generate distinct calcium dynamics in the postsynapse. Moreover, as described above, GluN2A CTD allows unique intracellular molecular associations with proteins like kinases and phosphatases and synaptonuclear messengers that intrinsically direct the plasticity signaling [33,75,108]. Recently it was also reported a specific metabotropic function of GluN2A-containing NMDAR in mediating glycine-induced potentiation of AMPAR currents through the activation ERK1/2 signaling [109].…”

“…Synaptic NMDARs mainly mediate pro-survival and synaptic plasticity pathways, whereas extrasynaptic NMDARs are mostly responsible for glutamate excitotoxicity and are detrimental for neuronal functions [23,31]. Furthermore, the balance in synaptic GluN2-type subunits is responsible for adequate glutamatergic neurotransmission, which is altered in several neurological disorders and which is linked to the pathophysiology of brain diseases [22,32,33]. Therefore, understanding the molecular mechanisms regulating NMDAR subunit composition at synapses, such as membrane insertion, and assembly and removal of specific regulatory subunits, represents a pharmacological challenge for the setting up of new therapeutic strategies for neurological disorders where NMDARs play a pivotal role [34,35].…”

Recent progress in allosteric modulators for GluN2A subunit and development of GluN2A‐selective nuclear imaging probes

“…NMDA receptors in the central nervous system (CNS) are capable to reshape the structure and function of synapses based on specific patterns of neuronal activities, which was considered to underlie higher cognitive processes . Together with other NMDA subunit receptors, the physiological function of the GluN2A subunit is related to synaptic plasticity, learning, and memory . In the mature brain, GluN2A is abundantly expressed in all regions of the CNS, particularly in hippocampus and cortex .…”

“…It appears as hetero‐dimeric GluN1/GluN2A or hetero‐trimeric GluN1/GluN2A/GluN2B receptors and is predominately located in the synapses . The dysfunction of GluN2A subunit is associated with various neurological diseases, such as schizophrenia, mood disorder, Parkinson's disease (PD), and Alzheimer's disease (AD) …”

Identifying the Role of GluN2A in Cerebral Ischemia

“…However, the role of GluN2A in cerebral ischemia remains controversial (Sun et al, 2016). Notably, previous studies of cerebral ischemia have ignored the influence of the triheteromeric GluN1/2A/2B receptor despite the fact that this receptor accounts for a large proportion of the NMDARs in the adult forebrain.…”