Glutamate ionotropic receptor NMDA type subunit 2D (GluN2D) (GluN2D)

GluN2D-containing NMDA receptors are heterotetrameric ligand-gated ion channels composed of two GluN1 subunits and at least one GluN2D subunit, encoded by the GRIN2D gene (UniProt Q14957). These receptors are distinguished by their exceptionally slow deactivation kinetics and reduced sensitivity to magnesium blockade, allowing them to mediate prolonged excitatory postsynaptic currents even at hyperpolarized membrane potentials (Paoletti et al., 2013). In the adult brain, GluN2D expression is highly localized to specific regions such as the basal ganglia, thalamus, and brainstem, and is notably prevalent on parvalbumin-positive inhibitory interneurons where it regulates cortical inhibitory tone (Perszyk et al., 2020). Pathologically, gain-of-function mutations in the GRIN2D gene are linked to severe developmental and epileptic encephalopathies, while reduced GluN2D signaling is implicated in the pathophysiology of schizophrenia and treatment-resistant depression (Burnashev & Szepetowski, 2015). Therapeutic strategies involve the use of selective antagonists like DQP-1105 or positive allosteric modulators like CIQ to fine-tune glutamatergic transmission, offering a more targeted approach than non-selective NMDA receptor blockers like ketamine (Mullasseril et al., 2010).

Other names

NR2DGRIN2DN-methyl-D-aspartate receptor subunit 2DGlutamate receptor subunit epsilon-4NMDAR2DGluR epsilon 4

Drugs targeting GluN2D-containing NMDA receptors typically act as non-competitive pore blockers, competitive antagonists at the glutamate or glycine binding sites, or as allosteric modulators that either enhance (PAMs) or inhibit (NAMs) channel opening frequency and duration to restore circuit balance (Paoletti et al., 2013; Perszyk et al., 2020).