GluN2D

GluN2D, also known as NR2D, is a subunit of NMDA-type glutamate receptors. It is encoded by the GRIN2D gene and contributes to the formation of functional NMDA receptors when paired with NR1 subunits (encoded by GRIN1). Receptors containing GluN2D can assemble as di-heteromeric GluN1/GluN2D receptors or as more complex multi-subunit assemblies with other NR2 subunits, and the subunit composition influences channel properties and pharmacology.

GluN2D expression is developmentally regulated. During early development it is relatively abundant in many brain regions, and in the mature brain it is prominently present in select circuits such as certain thalamic nuclei and brainstem neurons, with persistent expression in some interneuron populations and, in some species, in retina and other regions. This restricted regional and developmental pattern contributes to the unique functional roles of GluN2D-containing receptors.

Biophysically, GluN2D-containing NMDA receptors exhibit distinct properties compared with receptors that contain other NR2 subunits. They tend to show slower deactivation kinetics, which can prolong synaptic currents, and they display a different sensitivity to voltage-dependent magnesium block at subthreshold potentials. They also have distinct pharmacological profiles, including different sensitivities to endogenous modulators and to subunit-selective drugs compared with NR2A- or NR2B-containing receptors.

Functionally, the presence of GluN2D influences synaptic plasticity and network excitability in the circuits where it is expressed, contributing to developmental maturation of neural circuits and potentially to plastic changes in adulthood in certain regions. Dysregulation of GluN2D signaling has been explored in models of developmental and neurological disorders, making GluN2D a focus of interest for targeted modulation.

Therapeutically, GluN2D is considered a potential target for selective modulation of NMDA receptor activity. Research continues into compounds that preferentially interact with GluN2D-containing receptors, but there are no clinically approved drugs that selectively target this subunit as of now.