The N-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and kainate receptors. NMDA receptors (NMDARs) are glutamate-gated cation channels with high calcium permeability that play important roles in many aspects of the biology of higher organisms. They are critical for the development of the central nervous system (CNS), generation of rhythms for breathing and locomotion, and the processes underlying learning, memory, and neuroplasticity. Consequently, abnormal expression levels and altered NMDAR function have been implicated in numerous neurological disorders and pathological conditions. NMDAR hypofunction can result in cognitive defects, whereas overstimulation causes excitotoxicity and subsequent neurodegeneration. Therefore, NMDARs are important therapeutic targets for many CNS disorders including stroke, hypoxia, ischemia, head trauma, Huntington’s, Parkinson’s, and Alzheimer’s diseases, epilepsy, neuropathic pain, alcoholism, schizophrenia, and mood disorders. To date, drugs targeting NMDARs have had only limited success clinically due to poor efficacy and unacceptable side effects, including hallucinations, catatonia, ataxia, nightmares, and memory deficits. NMDARs are unique among ligand-gated ion channels in that their activation requires binding of two coagonists, glycine and L-glutamate. Glycine is sometimes cited in the literature as an NMDAR modulator—to set it apart from the agonist L-glutamate, but as explained below, their binding sites are structurally similar and seem to play equivalent roles in receptor activation. Physiologically, however, glycine and glutamate have distinct functions. While L-glutamate is released from specific presynaptic terminals, low concentrations of ambient glycine present at the synapse are thought to be sufficient to allow receptor activation. Because glycine plays a more modulatory role in vivo, while glutamate is the ‘active’, released neurotransmitter, the glycine and glutamate binding sites on the NMDAR represent two distinct therapeutic targets. However, the binding of the ligands is typically not sufficient to open the channel as it may be blocked by Mg2+ ions which are only removed when the neuron is sufficiently depolarized. Thus, the channel acts as a “coincidence detector” and only once both of these conditions are met, the channel opens and it allows positively charged ions (cations) to flow through the cell membrane. Ca2+ flux through NMDA receptors in particular is thought to be critical in synaptic plasticity, a cellular mechanism for learning and memory, due to proteins which bind to and are activated by Ca2+ ions. Overactivation of NMDA receptors, causing excessive influx of Ca2+ can lead to excitotoxicity. Excitotoxicity is implied to be involved in some neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease.

NMDA References