NMDA receptors (NRs) mediate fast excitatory transmission in the brain. Their activation is critical for the normal development, maintenance and continual remodeling of excitatory synapses. Excessive NR activity is a disease mechanism in stroke, chronic pain, epilepsy, and neurodegenerative disease, whereas insufficient NR signaling has been involved with schizophrenia and cognitive disorders. Numerous endogenous and pharmacologic agents modulate NR activities and are potential candidates for therapeutic intervention. The mechanisms governing the allosteric control of NR activity are poorly understood and empirical attempts to control NR function have so far yielded disappointing results. The OBJECTIVE is to understand how allosteric modulators control NR physiologic functions in terms of molecular mechanisms, integration and consequences on synaptic physiology.
The AIMS addressed in this proposal are to: i) characterize individual NR allosteric modulators in terms of their effects on NR gating dynamics and on non-stationary macroscopic behaviors; ii) establish how multiple allosteric signals are integrated to result in responses with distinct signaling profiles; and iii) investigate how allosteric modulation of NR responses impacts on synaptic physiology. First, using kinetic analysis of single-channel currents and statistical modeling we will identify and quantify the actions of individual modulators on NR elementary kinetic transitions during gating. These measured rate constants are intrinsically rich with mechanistic information; in addition they can predict modulator effects on NR macroscopic behaviors and on NR- mediated synaptic function. These predictions will be verified by measuring ensemble NR responses to patterned stimulation in excised membrane patches and by measuring evoked NR synaptic responses in brain slices. For NRs whose activation reaction is complex, this approach is entirely novel and may identify effective means to modulate specific receptor functions in separation of each other. Taken together the results will help to compile an integrated mechanistic view of how allosteric control of NR activity impacts synaptic physiology. This view should suggest new, combinatorial approaches to specifically target harmful receptor behaviors while preserving the critical functions played by NRs . ? ? ?
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