Neurotransmitters, neuropeptides and hormones regulate a large number of physiological responses through their interaction with specific receptors. It is the activated receptor which initiates the intracellular events which finally causes the physiological response. The receptor is, therefore, at the center of all neuronal activities and its mode of action is basic to our understanding of mental health. Many different receptors exist. In the last two years, the successful cloning of some of them has led to the proposition of a new concept regarding their multiplicity. This concept states that although each neuroreceptor is different in its primary amino acid sequence, all the neuroreceptors can be classified into two classes, the ligand-gated ion channels and the G protein-coupled receptors. The receptors in these two classes share significant degree of sequence similarity and the same membrane topology, they are members of two large gene families. The G protein-coupled receptors constitute a predominant class of neuroreceptors, from which several members have already been cloned. Using a technical strategy based on the sequence similarities expected to exist between the G protein-coupled receptors, we have cloned and sequenced a new receptor which has all the characteristics of a G protein-coupled receptor. This receptor is expressed in the brain, in the pituitary, in the kidney but not in several peripheral organs such as the liver. This receptor has several characteristics of the dopamine D2 receptor. We propose to reach two major goals: the first is to find the ligand specificity of this receptor and the other is to perform a molecular study of this receptor to establish the foundations on which its structure-activities relationships can be analyzed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH045614-02
Application #
3385409
Study Section
Neurology C Study Section (NEUC)
Project Start
1989-05-01
Project End
1992-03-31
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
2
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
Civelli, O; Bunzow, J R; Grandy, D K (1993) Molecular diversity of the dopamine receptors. Annu Rev Pharmacol Toxicol 33:281-307
Grandy, D K; Leduc, R; Makam, H et al. (1992) Nucleotide and deduced amino acid sequence of bovine adrenal medulla chromogranin B (secretogranin I). Cell Mol Neurobiol 12:185-92
Grandy, D K; Civelli, O (1992) G-protein-coupled receptors: the new dopamine receptor subtypes. Curr Opin Neurobiol 2:275-81
Civelli, O; Bunzow, J R; Zhou, Q Y et al. (1992) The diversity of the dopamine receptors. NIDA Res Monogr 126:23-33
Liu, Y F; Civelli, O; Grandy, D K et al. (1992) Differential sensitivity of the short and long human dopamine D2 receptor subtypes to protein kinase C. J Neurochem 59:2311-7
Liu, Y F; Civelli, O; Zhou, Q Y et al. (1992) Cholera toxin-sensitive 3',5'-cyclic adenosine monophosphate and calcium signals of the human dopamine-D1 receptor: selective potentiation by protein kinase A. Mol Endocrinol 6:1815-24
Zhou, Q Y; Li, C; Civelli, O (1992) Characterization of gene organization and promoter region of the rat dopamine D1 receptor gene. J Neurochem 59:1875-83
Grandy, D K; Allen, L J; Zhang, Y et al. (1992) Chromosomal localization of three human D5 dopamine receptor genes. Genomics 13:968-73
Mansour, A; Meador-Woodruff, J H; Zhou, Q et al. (1992) A comparison of D1 receptor binding and mRNA in rat brain using receptor autoradiographic and in situ hybridization techniques. Neuroscience 46:959-71
Zhou, Q Y; Li, C; Olah, M E et al. (1992) Molecular cloning and characterization of an adenosine receptor: the A3 adenosine receptor. Proc Natl Acad Sci U S A 89:7432-6

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