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Glutamate is the most abundant excitatory neurotransmitter in the CNS. The excitatory effects of glutamate are mediated by ionotropic and metabotropic receptors. The NMDA receptors (NMDARs) are glutamate-gated cation channels that are highly permeable to calcium (Ca2+) and are essential for regulation of synaptogenesis, use-dependent synaptic remodeling, and long-term plastic changes in synaptic strength. Excessive NMDAR activation leads to excitotoxicity, which results in cell loss in a wide range of acute, degenerative, and demyelinating neurologic disorders. NMDAR-mediated synaptic plasticity may contribute to levodopa-induced dyskinesia, drug addiction, and neuropathic pain; impaired NMDAR function may contribute to cognitive impairment in dementia and schizophrenia. Not surprisingly, the NMDARs are a very attractive therapeutic target. A characteristic syndrome resulting from autoantibodies against NMDARs emphasizes the critical role of these receptors in cognition, behavior and motor, respiratory, and autonomic control. Over the past several years, there have been important advances in the understanding of the molecular composition, trafficking, and distribution of these receptors well as the differential effects of NMDAR subtypes on cell survival and plasticity. There have been recent excellent reviews on these subjects.1,–,10
STRUCTURAL ORGANIZATION, CHANNEL PROPERTIES, AND MODULATION OF NMDARS
Composition.
NMDARs are heteromeric complexes composed of 4 subunits derived from 3 related families: NR1, NR2, and NR3.1,–,5 According to the current proposed nomenclature, these subunits are termed GluN1, GluN2, and GluN3, respectively.11 The classic nomenclature will be used in this review. The NR1 is an obligatory subunit that combines with NR2 or NR3 subunits to form a functional receptor. The NR1 subunit gene can be alternatively spliced to produce 8 distinct NR1 isoforms. Separate genes produce 4 types of NR2 (NR2A–D) and 2 types of NR3 (NR3A–B) subunits.12 The typical NMDAR requires consists of 2 NR1 subunits, which bind glycine, and 2 NR2 subunits, which bind glutamate …
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