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 function and disease states. My laboratory focuses mainly on synaptic physiology, specifically those synapses that use glutamate as their neurotransmitter. Glutamate receptors (GluRs) 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. When dysfunctional, GluRs have also been implicated in numerous psychiatric disorders such as schizophrenia as well as in acute and chronic cell death including that associated with various neurodegenerative diseases such as Alzheimer's and Parkinson's disease. The goal of the present proposal is to define GluR structure-function, focusing mainly on the ion channel component of these ligand-gated ion channels. Such information is key to understanding the 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 scanning, chimeras, protein chemistry, available crystal structures, fast agonist application, and whole-cell, outside-out patches, and single channel recordings. Specific Aim#1 will study the dynamics of the linker regions coupling the ligand-binding domain to M3, the major transmembrane gating domain. This region represents a critical juncture regulating receptor function and hence sites for modulating receptor dynamics under pathological states. Specific Aim#2 will study the functional and structural contribution of the M4 segment to channel function. All mammalian GluRs subunits have a transmembrane segment, M4, located C-terminal to the core of the ion channel (M1-M3). M4 is a necessary requirement for mammalian GluR function. Defining its contribution to this process will clarify fundamental mechanisms of gating in GluRs. Specific Aim#3 will further pursue issues related to channel gating specifically to desensitization, focusing on electrostatic interactions between the ion channel and the ligand-binding domain. This work will define fundamental principles of GluR structure-function and provide new tools and insights into means to attenuate the cell death GluR mediate under psychiatric states and pathological conditions. PROJECT NARRATIVE: Synapses mediate the transfer of information in the brain and are at the center of how we think, act and learn. Many drugs that have proven successful in the treatment of brain diseases such Alzheimer's and Parkinson's Diseases and mental illness act on synapses so they are a major focus of medical and pharmaceutical research. Our work studies one element -glutamate receptors- found at the most wide spread excitatory synapse in the mammalian brain, trying to define how this element carries out its function and how it might be modulated in disease states.