N-methyl-D-aspartate receptor GluN1-GluN2D (GluN1-GluN2D NMDAR)

The N-methyl-D-aspartate (NMDA) receptor GluN1-GluN2D is a specific heterotetrameric subtype of ionotropic glutamate receptors, composed of two glycine-binding GluN1 subunits and two glutamate-binding GluN2D subunits [1, 12]. It is distinguished by unique biophysical properties, including an exceptionally slow deactivation time course, low single-channel open probability, and reduced sensitivity to magnesium blockade compared to other NMDA receptor subtypes [1, 12, 13]. This receptor is predominantly expressed in the basal ganglia, such as the subthalamic nucleus and substantia nigra, as well as on GABAergic interneurons in the hippocampus and prefrontal cortex [1, 2, 11]. It plays a critical role in regulating neuronal excitability, synaptic plasticity, and the balance between excitation and inhibition in neural circuits [4, 6, 9]. Recent research has identified the GluN1-GluN2D receptor as a primary mediator of the rapid antidepressant effects of ketamine, which preferentially targets these receptors on interneurons to disinhibit excitatory networks [4, 5, 8]. Additionally, dysfunction or overactivation of this receptor is implicated in schizophrenia, Parkinson's disease, epilepsy, and neuropathic pain, making it a high-interest target for subtype-selective therapeutic intervention [3, 9, 11, 22].

Other names

NR1/NR2DNMDAR1/NMDAR2DGRIN1/GRIN2D complexGluN1/GluN2D heterotetramerGlutamate receptor ionotropic NMDA 1/2D

Non-competitive antagonism, negative allosteric modulation, positive allosteric modulation, and open-channel block [1, 5, 8, 19, 21].