The overall objective of this research program is to identify the molecular mechanisms of the agonist-dependent regulation of responsiveness of dopamine (DA) receptors. The molecular cloning of many subtypes of DA receptors makes it possible to compare the regulation of defined populations of receptors on identical cell backgrounds. Furthermore, the structural features of the receptors that specify the types of regulatory responses observed can be determined by construction of mutant or chimeric receptors. It is crucial that we understand the mechanisms of regulation of DA receptors, since idiopathic or drug-induced changes in the responsiveness of DA receptors are thought to be involved in the pathophysiology or treatment of psychiatric and movement disorders such as schizophrenia, parkinsonism, and tardive dyskinesia.
The specific aims of the project are as follows: 1a) The effect of prolonged exposure to agonists on the coupling of DA D1 receptors to adenylyl cyclase will be assessed. Both homologous and heterologous components of regulation will be assessed. In addition, regulatory responses of recombinant and endogenous receptors will be compared. 1b) The structural determinants of the sensitivity of coupling of DA receptors to adenylyl cyclase will be assessed by the construction of mutant Dl receptors in which potential sites of phosphorylation are eliminated. A special emphasis of this aim will be to distinguish structural features of receptors necessary for homologous regulation from those necessary for heterologous regulation. 2a) Agonist-dependent regulation of the density of Dl, D2, and D3 receptors will be characterized. Regulation of endogenous and recombinant Dl and D2 receptors will be compared. A key objective is to determine if agonist-induced proliferation of D2 and D3 receptors results from altered synthesis or degradation of receptors. 2b) The structural determinants of agonist-dependent regulation of Dl, D2, and D3 receptor density will be identified by the characterization of Dl/D2 and Dl/D3 chimeric receptors and receptors with point mutations.
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