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A D1/D2 chimeric dopamine receptor mediates a D1 response to a D2-selective agonist
R G MacKenzie1, M E Steffey, A M Manelli
1Neuroscience Research Division, Abbott Laboratories, Abbott Park, IL 60064.
FEBS Letters
|May 24, 1993
Summary
Researchers investigated dopamine receptor subtype selectivity using D1/D2 chimeric receptors. Findings suggest specific transmembrane regions in the D2 receptor are crucial for selective agonist binding, like quinpirole.
Area of Science:
- Pharmacology
- Neuroscience
- Molecular Biology
Background:
- Dopamine receptors (D1 and D2) are G-protein coupled receptors with seven transmembrane (TM) regions.
- While dopamine binds non-selectively, many compounds exhibit high subtype selectivity.
- Understanding these selectivity determinants is key for drug development.
Purpose of the Study:
- To identify regions within dopamine D1 and D2 receptors responsible for subtype-specific ligand binding.
- To investigate how chimeric receptor constructs influence the binding and agonist properties of selective compounds.
Main Methods:
- Creation and transfection of plasmid constructs encoding D1 or D1/D2 chimeric receptors into cells.
- Study of binding and agonist properties of various dopamine receptor ligands.
- Analysis of structure-activity relationships for subtype selectivity.
Main Results:
- Dopamine binds with equal affinity to both D1 and D2 receptors.
- The D2-selective agonist quinpirole demonstrated significant selectivity.
- Evidence suggests that transmembrane domains VI and VII of the D2 receptor are critical for quinpirole's selective binding.
Conclusions:
- Specific transmembrane regions of the D2 dopamine receptor confer selectivity for certain agonists.
- Transmembrane domains VI and VII play a crucial role in the selective binding of quinpirole to the D2 receptor.