Related Experiment Videos
Dopamine receptor oligomerization visualized in living cells.
Brian F O'Dowd1, Xiaodong Ji, Mohammad Alijaniaram
1Department of Pharmacology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. brian.odowd@utoronto.ca
The Journal of Biological Chemistry
|August 24, 2005
Summary
G protein-coupled receptors form oligomers. Receptor conformation influences dopamine receptor oligomer dynamics, revealing how conformational changes affect receptor interactions and cellular localization.
Area of Science:
- Pharmacology
- Cell Biology
- Biochemistry
Background:
- G protein-coupled receptors (GPCRs) exist as oligomers.
- Dopamine receptors are key GPCRs involved in various physiological processes.
- Understanding GPCR oligomerization dynamics is crucial for drug development.
Purpose of the Study:
- To visualize dopamine receptor oligomers in living cells.
- To investigate the role of receptor conformation in oligomer association and dissociation.
- To explore the impact of ligands on dopamine receptor oligomer stability.
Main Methods:
- Utilized a modified D1 dopamine receptor with a nuclear localization signal (NLS) for cellular trafficking studies.
- Employed inverse agonists and antagonists like (+)-butaclamol to modulate receptor localization and oligomerization.
- Investigated homooligomerization of D1 receptors and heterooligomerization between D1 and D2 dopamine receptors.
Main Results:
- D1-NLS trafficked to the nucleus, with inverse agonists blocking translocation.
- Homooligomers of D1 receptors co-translocated to the nucleus.
- Conformational heterogeneity, induced by drug treatment or receptor mutation, disrupted oligomer integrity.
- Robust heterooligomerization between D1 and D2 receptors was observed, resistant to disruption by inverse agonists.
- D2 did not heterooligomerize with a conformationally altered D1 mutant, suggesting an impaired interaction interface.
Conclusions:
- Receptor conformation is a critical determinant of dopamine receptor oligomer stability.
- Homogeneous receptor conformation maintains oligomer integrity, while heterogeneity disrupts it.
- Ligand-binding pocket occupancy by inverse agonists induces conformational changes affecting oligomerization.
- Novel insights into dopamine receptor assembly and the impact of ligand-bound states on GPCR oligomer dynamics.