GRIN2B

NMDA receptors

N-methyl-D-aspartate (NMDA) receptors are a class of ionotropic glutamate receptors. The NMDA receptor channel has been shown to be involved in long-term potentiation, an activity-dependent increase in the efficiency of synaptic transmission thought to underlie certain kinds of memory and learning. NMDA receptor channels are heterotetramers composed of two molecules of the key receptor subunit NMDAR1 (GRIN1) and two drawn from one or more of the four NMDAR2 subunits: NMDAR2A (GRIN2A), NMDAR2B (GRIN2B), NMDAR2C (GRIN2C), and NMDAR2D (GRIN2D). The NR2 subunit acts as the agonist binding site for glutamate, one of the predominant excitatory neurotransmitter receptors in the mammalian brain.

Function

NR2B has been associated with age- and visual-experience-dependent plasticity in the neocortex of rats, where an increased NR2B/NR2A ratio correlates directly with the stronger excitatory LTP in young animals. This is thought to contribute to experience-dependent refinement of developing cortical circuits.

Engineered to overexpress GRIN2B in their brains, mice and rats exhibit improved mental function. The "Doogie" mouse performed twice as well on one learning test.

Ligands

• Besonprodil
• CERC-301, a selective NR2B receptor antagonist
• Eliprodil
• Ethanol - apparent induction of dephosphorylation of the NR2B Tyr1472 residue by STEP, leading to reduced receptor function
• Ifenprodil
• Rislenemdaz
• EVT-101, a selective NR2B receptor antagonist. This compound was tested as a potentially fast-acting antidepressant. In 2011 it was voluntarily withdrawn from a Phase II clinical study in treatment-resistant depression due to an unsatisfactory toxicity profile.
• Felbamate, an anticonvulsant that is also a positive allosteric modulator for the GABAA receptor
• Ro-25-6981 (also known as MI-4), a selective NR2B receptor antagonist
• Traxoprodil, a selective NR2B receptor antagonist
• Toluene - noncompetitive antagonist

Interactions

GRIN2B has been shown to interact with:

• Actinin, alpha 2,
• DLG2,
• DLG3,
• DLG4,
• EXOC4,
• LIN7B, and
• RICS.

References

References

1. (May 1992). "Heteromeric NMDA receptors: molecular and functional distinction of subtypes". Science.
2. "Entrez Gene: GRIN2B glutamate receptor, ionotropic, N-methyl D-aspartate 2B".
3. (July 2003). "Two forms of synaptic plasticity with distinct dependence on age, experience, and NMDA receptor subtype in rat visual cortex". The Journal of Neuroscience.
4. (September 1999). "Genetic enhancement of learning and memory in mice". Nature.
5. (October 2009). "Genetic enhancement of memory and long-term potentiation but not CA1 long-term depression in NR2B transgenic rats". PLOS ONE.
6. (2008-02-14). "The Effects of a Novel NMDA NR2B-Subtype Selective Antagonist, EVT 101, on Brain Function". ClinicalTrials.gov.
7. (May 2024). "Phase II study with NR2B sub-type selective NMDA antagonist in treatment-resistant depression voluntarily terminated". evotec.com.
8. (January 1997). "Competitive binding of alpha-actinin and calmodulin to the NMDA receptor". Nature.
9. (June 2002). "Inward rectifier K+ channel Kir2.3 is localized at the postsynaptic membrane of excitatory synapses". American Journal of Physiology. Cell Physiology.
10. (September 1997). "Binding of neuroligins to PSD-95". Science.
11. (June 2003). "NMDA receptor trafficking through an interaction between PDZ proteins and the exocyst complex". Nature Cell Biology.
12. (June 2002). "Selectivity and promiscuity of the first and second PDZ domains of PSD-95 and synapse-associated protein 102". The Journal of Biological Chemistry.
13. (April 1998). "CRIPT, a novel postsynaptic protein that binds to the third PDZ domain of PSD-95/SAP90". Neuron.
14. (September 1995). "Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95". Science.
15. (June 1999). "Characterization of MALS/Velis-1, -2, and -3: a family of mammalian LIN-7 homologs enriched at brain synapses in association with the postsynaptic density-95/NMDA receptor postsynaptic complex". The Journal of Neuroscience.
16. (July 2003). "p250GAP, a novel brain-enriched GTPase-activating protein for Rho family GTPases, is involved in the N-methyl-d-aspartate receptor signaling". Molecular Biology of the Cell.