Functional Architecture of Glutamate Receptor Channels

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DESCRIPTION (provided by applicant): The long-term objective of my laboratory is to understand the molecular mechanisms underlying signaling in the brain, especially as it relates to higher brain functions and disease states. My laboratory focuses mainly on synaptic physiology, specifically those synapses that use glutamate as their neurotransmitter. Glutamate receptors (GluR) mediate basic information processing in the brain and contribute to the cellular and molecular mechanisms underlying learning and memory, the development and maintenance of cellular connections, and pain transduction and perception. They have also been implicated in acute and chronic celt death, including that associated with numerous neurological diseases. The goal of the present proposal is to investigate the structural basis of channel gating in GluRs. Such information is key to understanding the fundamental role of GluRs in brain function as well as the development of drugs that attenuate the cell death they mediate under pathological conditions. This issue will be studied in recombinant GluRs using a variety of techniques including site-directed mutagenesis, cysteine substitutions, channel blockers, fast agonist application, and whole cell and single channel analysis. Aim 1 will study the structure of the extracellular vestibule in GluR channels, including how it relates to an asymmetry between subunits. Given the functional significance of the extracellular vestibule--it contains sites for pore blockers with therapeutic potential--defining this domain is essential. This work also forms the basis for Aim2, where we will study more specifically the conformational changes in the extracellular vestibule during gating. These conformational changes couple ligand binding to channel opening and therefore represent fundamental features of their function. Aim3 will further pursue issue related to channel gating specifically to desensitization. These experiments will provide key insights into an important physiological process. This work will define fundamental principles of structure/function in GluR channels and provide new tools and insights into means to attenuate the cell death GluR mediated under pathological conditions.