N-methyl D-aspartate receptors are a subtype of glutamate receptors that mediate excitatory signal transmission in the mammalian central nervous system. Their primary function involves converting the chemical signal into an electrical signal, i.e. glutamate binding to an extracellular domain in the receptor triggers the formation of cation permeable transmembrane channels in the receptor. Given the importance of these receptors in mediating a number of physiological processes and the need to modulate their function in disease states, the primary questions are how does the agonist activate the protein and how can this mechanism be modulated. The NMDA receptors are modulator in structure consisting of an amino terminal domain, agonist binding domain, channel segments and the C-terminal domains. Here we propose to study the communication between the domains and their role in dictating activation and allosteric modulation. Specifically we will investigate the role o the interactions between GluN1 agonist binding domain with the GluN2 subunit in controlling agonist binding domain dynamics and extent of activation (specific aim 1) using a combination of luminescence resonance energy transfer, smFRET, and electrophysiology. We will also investigate the pathway for allosteric modulation by establishing the conformational changes starting at the amino terminal domain through the agonist binding domain and study the changes in dynamics in the extracellular domains during the allosteric modulation (specific aim 2). The spectroscopic investigations will be complemented by electrophysiological measurements investigating the changes in function induced by alterations at the interface between the domains. These functional and structural investigations will provide a comprehensive understanding of the conformational pathway as well as role of dynamics in activation and allosteric modulation in NMDA receptor function.
The NMDA subtype of glutamate receptors are the main mediators of excitatory synaptic transmission. These receptors are involved in learning and memory and a number of other physiological processes, and over or under stimulation of the receptors leads to neurological disorders such as stroke, seizures, Parkinson's disease etc. Here we will study the mechanism of activation and modulation of these receptors
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