NMDA receptors play critical roles during the normal development and function of central synapses. Mutant receptors were recently identified in patients with neurologic and psychiatric conditions and were found to be causal to the diagnosed dysfunctions. The long-term objective of this project is to correlate functional receptor states postulated by the established kinetic mechanism with structural conformations. Specifically, the two aims proposed here will integrate molecular dynamics simulations and electrophysiological measurements to delineate plausible conformations for the adult NMDA receptor isoform in closed and open conformations and for a series of rationally-targeted and naturally occurring, pathologic NMDA receptor mutants. Results will elucidate the NMDA receptor gating reaction and the mechanism by which single-residue substitutions change structure and cause dysfunction.
NMDA receptors are proteins with critical roles in the normal development of central synapses, but also in psychiatric conditions such as epilepsy, schizophrenia, addiction and chronic pain, and in neurodegenerative pathologies such as stroke, Alzheimer?s, Parkinson?s, and Huntington?s diseases. The long-term objective of this project is to assign structural conformations for the main functional states of the NMDA receptor, and to delineate the mechanism by which these states interconvert during normal and disease states, and thus generate basic knowledge necessary for rational therapies.
