This grant is requested to support a basic research program aimed at elucidating at the molecular level the nature, mode of functioning and regulation of the specific receptors for dopamine. Physiologically, dopamine exerts effects such as regulation of hormone synthesis and secretion in the periphery and control of cognitive, affective and neuroendocrine functions in the central nervous system (CNS). For a long time, these effects of dopamine were thought to be mediated by only two distinct G protein-coupled receptor subtypes Dl and D2, coupled respectively to stimulation and inhibition of adenylyl cyclase. Recent developments from several experimental approaches but in particular molecular biology now suggest that the family of dopamine receptors will be much larger than previously anticipated. The cDNAs and genes of three distinct dopamine receptor subtypes have already been isolated. In order to characterized these systems, the work proposed in this application (six specific aims) can be divided into two main lines of investigations. First, we want to determine using the molecular biology approach the extent of this receptor family and determine the physiological significance of the apparent heterogeneity of receptors for dopamine. Second, we want to examine the biochemical mechanisms of action, regulation and interaction of the various dopaminergic receptor systems as they may underlie pathophysiological situations. In order to characterize these mechanisms at the molecular level we propose to develop procedures for the over-expression and purification of every member of this receptor. family using the baculovirus-infected insect cell system. Elucidation of the basic molecular mechanism of signal transduction and regulation of the different subtypes of dopamine receptors may help in understanding the etiology of certain CNS disorders such as schizophrenia, Parkinson's disease or peripheral disturbances such as hyperprolactinemia. This project constitutes an integral part of the overall long term objective of this laboratory to characterized at the molecular level the Various receptors for catecholamines.
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