The initial event in taste reception involves the interaction of the taste stimulus with the receptor cell plasma membrane. Previous studies have provided evidence that, for amino acid taste reception, the initial binding process takes place between the amino acid and a membrane-associated protein. In order to define the process of reception in detail and lay a foundation for further studies that can seek to correct receptor disease, these proteins that perform the recognition function must be characterized and isolated. To do this, specific inhibitors to the binding process need to be identified or developed. This proposal uses multi-disciplinary approaches (neurophysiology and biochemistry) to 1) identify compounds that act as inhibitors to the binding and transduction steps in taste, 2) produce monoclonal antibodies that act as agonists or antagonists against the receptor binding sites, and 3) characterize the inhibitor-receptor interactions using both biochemical and neurophysiological procedures with respect to affinity, specificity and type of competition. The animal model to be used for this work is the catfish since, unlike land vertebrates, it possesses a high density of receptors, is sensitive to very low concentrations of amino acids and has been used in a number of behavioral, neurophysiological and biochemical studies. Consequently, its taste-related characteristics are well documented. Neurophysiological studies will define the type of inhibition displayed by chemical inhibitors and inhibitory antibodies and allow their classification as either agonists or antagonists. Biochemical studies will define the characteristics (competitive - non-competitive) of the inhibitors in a binding assay and allow quantitative estimates of affinity of the inhibitors for the binding site. Both types of analyses will be used to determine specificity of the inhibitors against different classes of amino acid receptor sites, and to examine the enantiomeric specificity of each site. Once identified and their activity characterized and assessed, the agonists and antagonists can be used in further studies seeking to isolate the receptors or regulatory entities they inhibit.
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