This application presents a comprehensive research program aimed at characterizing a hormone/neurotransmitter receptor, its mechanism of action and its physiological regulation at the molecular level. The model system chosen for study is the anterior pituitary dopamine receptor. This receptor mediates the physiological effects of dopamine to inhibit prolactin secretion. There are three specific aims. 1) To characterize the biochemical mechanisms by which the binding of dopamine to its specific anterior pituitary receptor is transduced into the physiological response inhibition of prolactin secretion; 2) To solubilize, purify and characterize the dopamine receptors as well as identify the binding subunit of the receptor by affinity and photoaffinity labelling; 3) To determine the molecular mechanisms of endocrine regulation of the dopaminergic receptors and hence of dopaminergic responsiveness. Drawing on the previous experience with purification and photo-affinity labelling of the beta-adrenergic receptors, new specific procedures and probes will be developed for purification of the receptor protein itself in order to pave the way for the eventual complete biochemical and physicochemical characterization of the dopaminee receptor. These results and procedures should be widely applicable to other receptor/neurotransmitter systems such as those in the central nervous system. Moreover, the results should shed further light on our understanding of the endocrinological regulation of receptor expression in target tissues in particular with regard to the regulation of prolactin secretion. Such information will facilitate the development of new and more efficacious forms of treatment for endocrinological and autonomic disorders, particularly those which may involve altered prolactin secretion or dopaminergic function. This project constitutes an integral part of the overall long term objective of this laboratory to characterize at the molecular level the various catecholamine receptors. The results of these and other ongoing studies should therefore provide a comprehensive and fundamental understanding of how catecholamine responsiveness is mediated and modulated at the receptor level in both physiological and pathophysiological circumstances.
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