GluN2B

GluN2B, also known as NR2B, is a subunit of the NMDA-type glutamate receptor. It is encoded by the GRIN2B gene and combines with GluN1 subunits (and sometimes GluN2A in tri-heteromeric assemblies) to form functional NMDA receptors. These receptors are ligand-gated ion channels that require simultaneous binding of glutamate and a co-agonist such as glycine or D-serine, and are permeable to calcium.

GluN2B-containing receptors exhibit distinctive biophysical properties, including relatively high affinity for glutamate, slower deactivation kinetics, and strong regulation by phosphorylation and intracellular signaling proteins.

GluN2B-containing receptors are enriched in forebrain regions such as the cortex, hippocampus, and amygdala, with high expression during early development that gradually declines with age but persists in specific circuits.

Regulation and interactions: the cytoplasmic C-terminal tail binds scaffold proteins like PSD-95 and SAP102, linking receptors to signaling complexes. Phosphorylation by Src family kinases, CaMKII, PKA, and PKC modulates trafficking, channel opening, and synaptic localization. The N-terminal domain mediates allosteric regulation by divalent cations and ligands such as ifenprodil, which preferentially inhibits GluN2B-containing receptors.

Clinical significance: alterations in GRIN2B or GluN2B-containing NMDA receptors have been associated with neurodevelopmental disorders, intellectual disability, autism spectrum disorders, epilepsy, and schizophrenia risk. Pharmacological modulation of GluN2B is explored in research and potential therapies for stroke, neurodegenerative disease, and pain, though clinical applications face challenges due to the broad role of NMDA receptors in normal brain function.

Genetic variants: de novo missense mutations and copy-number variations in GRIN2B have been reported in affected individuals, with variable phenotypes.