nr1

NR1 is the obligatory subunit of NMDA receptors in mammals, encoded by the GRIN1 gene. It co-assembles with NR2 and sometimes NR3 subunits to form functional receptor complexes that mediate excitatory neurotransmission in the central nervous system. The NR1-containing receptors are widely expressed in the brain and are essential for the normal development and function of synapses.

The NR1 subunit provides the binding site for the co-agonist glycine, while the NR2 subunits bind glutamate. Activation of NMDA receptors requires both ligands, and the channel is permeable to sodium, potassium, and calcium ions. At resting membrane potential, magnesium blocks the channel, and calcium influx through NR1/NR2 receptors initiates intracellular signaling cascades that influence synaptic strength and plasticity.

NR1 exists in multiple splice variants that differ in their C-terminal cytoplasmic tails (and sometimes the N-terminal region). These isoforms influence receptor trafficking, surface expression, interactions with intracellular proteins, and regulatory properties, allowing tissue- and developmentally specific functions.

Functionally, NR1-containing NMDA receptors contribute to synaptic plasticity, learning, and memory, and are involved in activity-dependent strengthening and remodeling of synapses. They also participate in developmental processes and neuronal survival signaling.

Mutations and variants in GRIN1 have been linked to neurodevelopmental disorders, including intellectual disability, developmental delay, epileptic encephalopathy, and autism spectrum features. Such mutations can alter receptor function, trafficking, or expression, highlighting the NR1 subunit’s critical role in neural circuit operation.

NR1 forms heteromeric complexes with NR2 (and sometimes NR3) subunits, and its interactions with scaffolding and regulatory proteins modulate receptor localization and signaling. Neto1/ Neto2 proteins and intracellular binding partners such as PSD-95 contribute to the functional organization of NR1-containing receptors.