Molecular Physiology of NMDA Receptors

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Abstract N-methyl-D-aspartate (NMDA) receptor activity produces calcium-rich excitatory currents that control the physiology of central synapses. Ongoing excitatory transmission through NMDA receptors is essential for moment by moment consciousness and cognition. In addition, permeating calcium drives long-term changes in the strength of synapses to initiate learning and memory formation. Excessive NMDA receptor-mediated calcium entry kills neurons and is a disease mechanism in stroke and age-related chronic pathologies such as Alzheimer’s and Parkinson’s. Despite being sensitive to multiple small-molecule modulators, the potential of NMDA receptors as therapeutic targets remains unrealized due to insufficient knowledge about the structural changes that make their activation reaction. Moreover, recent advances in diagnosis with genetic sequencing has identified a large number of unique variants in patients with neuropsychiatric disorders. Many of these variants are causal to the disease, but the mechanism by which they affect the reaction mechanism, and therefore function is unknown. The overall objective of this research program is to describe the NMDA receptor activation, which consists of stochastic transitions between closed, open, and desensitized states, with a level of detail that integrates atomic- level structural information obtained from static receptor conformations with coarse-grained and atomistic molecular dynamic simulations. These structural results will be tested with kinetic and thermodynamic measurements of NMDA receptor current output. At the completion of the proposed study, we will have identified atomic structures representative for each of the three main functional states (closed, open, desensitized) and how these structures interconvert; will delineate key atomic interactions that control these changes in structure; and will describe how the dynamic distribution of receptors across this conformational landscape controls the patterns of depolarization and calcium influx produced by NMDA receptors. Furthermore, we will then interrogate the resulting integrated mechanism to examine how disease-related mutations and small-molecule modulators affect the conformational dynamics of receptors and how they alter the NMDA receptor current. The project will produce a congruent model that can be used to develop small-molecule modulators targeted to specific receptor conformations that would reduce calcium flux independently of excitatory action, and will guide therapeutic approaches for patients with dysfunctional NMDA receptor genetic variants.