Functional Characterization of an AMPA receptor: GluR3

Cornell University, Ithaca NY

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Abstract

DESCRIPTION (provided by applicant): Ionotropic glutamate receptors (iGluR's) are ligand gated ion channels that mediate most of the fast excitatory neurotransmission in the central nervous system. Aberrant function of glutamate neurotransmission can lead to neurological disorders. Drugs designed to target glutamate receptors have the potential to treat a number of neurological conditions. Understanding the relationship between the structure, function and dynamics of glutamate receptors is Important for the development of subtype selective pharmacological agents necessary to treat iGluR related disorders. Single channel electrophysiological studies completed on one specific AMPA receptor subtype (GluR3) will provide functional properties of these receptors induced by different agonists and can be used as a model for future studies on other ionotropic glutamate receptors. The first objective of these studies is to characterize the various levels of conductance classes at different ligand concentrations for a full agonist, glutamate, and a group of structurally related partial agonists, the willardiine compounds. The second objective is to model channel behavior and determine kinetic rates that best represent the mode of channel activation. Single channel data will be analyzed with different methods using QuB software that includes a hidden Markov model approach to event detection. The substrate model and kinetic rates will be compared between the full and partial agonists to determine any similarities or differences in channel function. The rat GluR3 gene has been stably transfected into HEK 293 cells and single channel currents will be measured using the cell attached method. Data will be obtained with an EPC7 amplifier and analog low pass filtered with a Bessel filter at a maximum of 10 kHz. By understanding the kinetics of these channels in the context of the structure of the ligand binding domain, new pharmacological agents can be designed to target a specific component of function. PUBLIC HEALTH RELEVANCE: Numerous acute and chronic neurological conditions involve the function of ion permeable glutamate receptors. However, limited knowledge pertaining to the function of these receptors restricts development of new selective pharmacological agents. Understanding various aspects of glutamate receptors, such as structure and function, will lead to better drug design and better treatment for the large population that suffer from neurological conditions.