NMDA receptor

NMDA Receptor Overview

• History Discovered in the 1960s; subunit selectivity found in the early 1990s; associated with neurological disorders.
• Structure Heterotetramers with GluN1, GluN2, and GluN3 subunits; various splice variants.
• Function Ion channel important for synaptic plasticity, learning, and memory; activation allows cations to flow through the cell membrane.
• Pharmacology Activity can be blocked by drugs like ketamine and nitrous oxide; overactivation can lead to neural death.
• Clinical Applications Balancing excessive activation, treating neurodegenerative disorders, and preventing neurotoxicity.

Mechanism of Action

• Gating Interaction with intracellular proteins via subunits; activation depends on glutamate, serine or glycine, and depolarization.
• Variants GluN1 has eight variants, GluN2 has four isoforms.
• Switches GluN2B to GluN2A and GluN2B to GluN2C transitions.
• Excitotoxicity Involvement in neurodegenerative disorders; dual nature based on location; differing cascade pathways.

Role in Neural Plasticity

• Signaling Pathways Activation varies in synaptic and non-synaptic receptors; regulation of p38 MAPK and involvement of ERK1/2 and Jacob.
• Neural Plasticity Influencing synaptic plasticity, triggering long-term potentiation and depression; involvement in LTD and LTP.
• Excitotoxicity Link to neurodegenerative conditions; unwanted side effects of antagonists; potential treatment approaches.

Ligands and Agonists

• Agonists Glutamic acid, glycine, and serine as endogenous agonists; D-serine regulation; examples of agonists like aspartic acid.
• Partial Agonists NMDA and 3,5-Dibromo-phenylalanine; development of rapastinel and apimostinel for antidepressant and analgesic effects.
• Antagonists Ketamine and other NMDA receptor antagonists; potential side effects like Olney’s lesions.

Clinical Applications and Pharmacology

• Pharmacology Blocking excessive activation; memantine as an uncompetitive antagonist; preventing excitotoxicity.
• Clinical Applications Challenges in utilizing antagonists for neuroprotection; balancing normal functions with blocking excessive activation; potential for treating neurodegenerative disorders.

NMDA receptor Data Sources