NMDA receptors

Abstract

The N-methyl-D-aspartate (NMDA) type glutamate receptors are abundant, ubiquitously distributed throughout the CNS, fundamental to excitatory glutamatergic transmission and critical for normal brain function. Activation of NMDA receptor is complex; both glutamate and glycine are required to open the ion channel and allow calcium entry. NMDA receptor is voltage dependently blocked by magnesium and depolarization is needed to remove this block. In the CNS synapses, NMDA receptors are localized in a highly organized subcellular fraction, the Post Synaptic Density (PSD), an electron dense and highly differentiated structure associated with the postsynaptic membrane, where clustering of ionotropic glutamate receptors to scaffolding proteins and signalling elements is dynamically regulated. To date, although molecular basis of glutamate toxicity remain uncertain, there is general agreement that NMDA subtype of ionotropic glutamate receptors plays a key role in mediating at least some aspects of glutamate excitotoxicity. NMDA receptor antagonists are effective in many experimental animal models of disease, and some of these compounds have moved into clinical trials. However, the initial enthusiasm for this approach has waned, because the therapeut ic ratio for most NMDA antagonists is poor, with significant adverse effects at clinically effective doses, thus limiting their utility. Understanding the biochemical properties of the multitude of NMDA receptor subtypes offers the possibility of developing more effective and clinically useful drugs. In fact, NMDA receptor is part of a postsynaptic signaling complex including kinases, and other signaling and scaffolding proteins. This finding may improve the identification of specific molecular targets whose pharmacological or genetic manipulation might lead to innovative therapies for both acute and neurodegenerative disorders.