Natural source compounds that differentiate between similar subtypes of receptor proteins are critical tools in modern neuroscience and often serve as valuable lead molecules for therapeutic applications. This has been particularly true with respect to lonotropic glutamate receptors, the receptors that underlie fast excitatory neurotransmission in the central nervous system; pharmacologically active glutamate receptor compounds have been isolated from a number of diverse organisms. Most recently, dysiherbaine (DH), a novel ligand for kainate (KA) and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type glutamate receptors, was isolated from the marine sponge Dysidea herbacea. DH was shown to be a potent convulsant with an unusually high affinity for a subset of KA receptors; this compound, as well as its natural and synthetic analogues, represents a novel set of tools for investigating biophysical and physiological properties of excitatory amino acid receptors. The diversity and complexity of glutamate receptor expression, as well as the central role of these proteins in brain function, underscore the importance of isolation and characterization of new pharmacological tools with unique selectivity profiles. This project will characterize a new set of pharmacological tools - DH and its analogues - and use these compounds to examine functional aspects of glutamate receptor activity at the biophysical and neuronal level.In the first specific aim, the biological activity of novel analogues of DH will be determined. In the second specific aim, we will use DH as a tool for understanding structure-function relationships of kainate receptors. Kainate receptor subunits exhibit a high degree of variability in their responses to DH, which affords an opportunity to use the marine toxin as a key probe for uncovering important functional domains of the receptor proteins. The third specific aim will be focused on determining the subunitcomposition of neuronal kainate receptors using a combined pharmacological and genetic approach, with our most important tools consisting of gene-targeted mice and subunit-selective marine toxins.
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