Various imidazoline and guanidinium derivatives elicit diverse cellular responses in both peripheral tissues and in the central nervous system that are often difficult to attribute to known receptor signalling systems. Such molecules also exhibit high affinity for membrane proteins (imidazoline binding sites) that are distinct from receptors for known hormones and recognize an endogenous bioactive substance(s) that mimics some of the effects of these compounds. These observations suggest a previously uncharacterized cell signalling system. However, the functionality of imidazoline binding sites remains unresolved. Unexpectedly and of particular significance, recent data indicate that two members of imidazoline binding proteins are identical to the A and B isoforms of monoamine oxidase (MAO), enzymes that catalyze catecholamine neurotransmitters and xenobiotics. The imidazoline binding domain on MAO is distinct from the enzyme active site that recognizes the mechanism based inhibitors such as pargyline and deprenyl and is not equally accessible in all tissues. The limited accessibility of the imidazoline domain on MAO-B is the focus of this application.
Specific Aims : 1. Identify the structural domains of monoamine oxidase interacting with imidazoline-guanidinium ligands. 2. Determine if there are structural differences in MAO-B in tissues where the enzyme exhibits differential accessibility of its imidazoline binding domain. 3. Determine if the apparent inaccessibility of the imidazoline binding site on Mao B in certain tissues involves interaction with cell specific accessory proteins or an endogenous masking substance. MAO is a therapeutic target in the management of certain mood disorders, the early phases of Parkinson's Disease and enzyme activity may contribute to the onset of other neurodegenerative disorders. The demonstration that some types of imidazoline binding proteins in humans are indeed monoamine oxidase isoforms suggests that MAO receives multiple regulatory inputs that may be of significance in the etiology and/or management of various disease states. Information generated from the proposed studies may implicate a novel approach to the regulation of this enzyme.
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