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.

Keywords: GluN2A and GluN2B; N-methyl-D-aspartate receptors (NMDARs); antagonists; compounds; neurodegeneration; neuroprotection.

Figure 1

N-methyl-D-aspartate receptor cation channel. For clarity, two of four subunits (NR1 and NR2) of a functional channel are depicted. Each subunit contains three transmembrane regions (M1, M3, and M4) and a re-entry loop (M2), which is believed to form the channel selectivity filter influencing cation selectivity. The known agonists (glutamate and glycine), allosteric modulatory sites (Zn²⁺, polyamine, and redox sites), and uncompetitive antagonist sites (Mg²⁺ and PCP) are depicted at approximate proposed positions [11].

Figure 2

Expressions of GluN1 and GluN2A–D mRNAs in postnatal development (sagittal sections) [13].

Figure 3

Crystal structure of amino terminal domains of the NMDA receptor subunits GluN1 and GluN2B in complex with ifenprodil (PDB ID: 5EWJ).

Figure 4

(a) NVP-AAM077; (b) crystal structure of GLUN1/GLUN2A ligand-binding domain in complex with glycine and NVP-AAM077 (PDB ID: 5U8C).

Figure 5

TCN.

Figure 6

MPX-004.

Figure 7

MPX-007.

Figure 8

Traxoprodil.

Figure 9

(a) Ro 25-6981; (b) triheteromeric NMDA receptor GluN1/GluN2A/GluN2B in complex with glycine, glutamate, Ro 25-6981, MK-801, and a GluN2B-specific Fab, at pH 6.5 (PDB ID: 5UP2).

Figure 10

(a) Memantine; (b) memantine-bound GluN1a-GluN2B NMDA receptors (PDB ID: 7SAD).

Figure 11

Radiprodil.

Figure 12

PD 174494.

Figure 13

PD 196860.

Figure 14

MK-0657 (CERC-301).

Figure 15

(a) EVT-101 (NCT01128452); (b) crystal structure of amino terminal domains of the NMDA receptor subunits GLUN1 and GLUN2B in complex with EVT-101 (PDB ID: 5EWM).

Figure 16

Ketamine.

Figure 17

Esketamine.

Figure 18

(a) Structure of the human GluN1-GluN2A NMDA receptor in complex with S-ketamine, glycine, and glutamate (PDB ID: 7EU7); (b) structure of the human GluN1-GluN2B NMDA receptor in complex with S-ketamine, glycine, and glutamate (PDB ID: 7EU8).