The long term objectives of this research are to understand the role(s) of dopamine (D2) receptor-activated signal transduction within defined cellular environments. D2 receptors are the site of action of agents in the treatment of severe neuropsychiatric disorders such as schizophrenia and Parkinson's disease. Inasmuch as many receptor responses are mediated by specific second messenger systems, the specific aims of this proposal are to define the effects and interactions of newly identified D2 receptor subtypes on signal transduction pathways. Gene transfer techniques will be utilized to create cell lines expressing either single or multiple receptor subtypes. Subsequently, the effects of receptor stimulation, blockade, and desensitization will be analyzed in terms of calcium metabolism. Effects on receptor number, coupling and subtype interactions will be quantified. Since the D2 receptor variants presumably couple to different G proteins with different effects on second messenger systems, a detailed examination of these subtypes will delineate the effects of dissimilarities and interactions on cellular signalling pathways. In an extension of these studies the effect of D2 receptor activation will be correlated with rapid genomic responses. D2 subtype specific cell lines will be examined for stimulus transcription coupled events. If changes in immediate-early response genes are present, further experiments elucidating the second messenger pathways involved in gene activation will be done. These studies will provide significant information on how receptor-mediated mechanisms give rise to long term changes within target cells. The ability to study defined combinations of expressed receptor subtypes should allow extrapolation to more complex biological systems.
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