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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH045372-06
Application #
2246541
Study Section
Neuropharmacology and Neurochemistry Review Committee (NPNC)
Project Start
1989-09-01
Project End
1999-08-31
Budget Start
1995-09-30
Budget End
1996-08-31
Support Year
6
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
Abraham, Antony D; Neve, Kim A; Lattal, K Matthew (2014) Dopamine and extinction: a convergence of theory with fear and reward circuitry. Neurobiol Learn Mem 108:65-77
Clayton, Cecilea C; Donthamsetti, Prashant; Lambert, Nevin A et al. (2014) Mutation of three residues in the third intracellular loop of the dopamine D2 receptor creates an internalization-defective receptor. J Biol Chem 289:33663-75
Rangel-Barajas, Claudia; Malik, Maninder; Taylor, Michelle et al. (2014) Characterization of [(3) H]LS-3-134, a novel arylamide phenylpiperazine D3 dopamine receptor selective radioligand. J Neurochem 131:418-31
Neve, K A; Ford, C P; Buck, D C et al. (2013) Normalizing dopamine D2 receptor-mediated responses in D2 null mutant mice by virus-mediated receptor restoration: comparing D2L and D2S. Neuroscience 248:479-87
Gantz, Stephanie C; Ford, Christopher P; Neve, Kim A et al. (2011) Loss of Mecp2 in substantia nigra dopamine neurons compromises the nigrostriatal pathway. J Neurosci 31:12629-37
Lan, Hongxiang; Liu, Yong; Bell, Michal I et al. (2009) A dopamine D2 receptor mutant capable of G protein-mediated signaling but deficient in arrestin binding. Mol Pharmacol 75:113-23
Lan, Hongxiang; Teeter, Martha M; Gurevich, Vsevolod V et al. (2009) An intracellular loop 2 amino acid residue determines differential binding of arrestin to the dopamine D2 and D3 receptors. Mol Pharmacol 75:19-26
Liu, Yong; Buck, David C; Neve, Kim A (2008) Novel interaction of the dopamine D2 receptor and the Ca2+ binding protein S100B: role in D2 receptor function. Mol Pharmacol 74:371-8
Liu, Yong; Buck, David C; Macey, Tara A et al. (2007) Evidence that calmodulin binding to the dopamine D2 receptor enhances receptor signaling. J Recept Signal Transduct Res 27:47-65
Watts, Val J; Neve, Kim A (2005) Sensitization of adenylate cyclase by Galpha i/o-coupled receptors. Pharmacol Ther 106:405-21

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