GRIN2A

GRIN2A is a human gene that encodes the GluN2A (NR2A) subunit of the NMDA-type glutamate receptor. The NMDA receptor is a ligand-gated ion channel that mediates calcium and sodium influx and is central to synaptic plasticity. In most forebrain regions, NMDA receptors are heterotetramers composed of two obligatory GRIN1 (NR1) subunits and two regulatory GRIN2 subunits, with NR2A and NR2B being the predominant types in mature cortex and hippocampus. The expression of NR2A increases with development, shifting the receptor subunit composition away from NR2B as neurons mature.

GluN2A-containing receptors bind glutamate at NR2 and require co-agonist glycine or D-serine at NR1; they have distinct kinetic and pharmacological properties, including reduced Mg2+ block at certain voltages and faster deactivation compared with NR2B-containing receptors. Functionally, they support synaptic plasticity, including long-term potentiation, and contribute to activity-dependent calcium signaling. The receptor complex associates with scaffolding proteins such as PSD-95, which anchors it at synapses and links it to intracellular signaling pathways.

Mutations in GRIN2A are associated with a spectrum of neurodevelopmental disorders, most notably epilepsy-aphasia syndrome and epileptic encephalopathy, often with language impairment and developmental delay. Reported variants can produce gain-of-function or loss-of-function effects on receptor activity, reflecting diverse pathogenic mechanisms. Diagnosis typically relies on molecular genetic testing, including targeted sequencing panels or exome sequencing. Understanding of GRIN2A-related disease is guiding interest in targeted therapies that modulate NMDA receptor activity, although clinical options remain limited.

In research, GRIN2A knockout and knock-in models help delineate the role of NR2A in synaptic maturation, plasticity, and learning, illustrating how subunit composition shapes receptor signaling and neuronal circuits.