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Folding efficiency is rate-limiting in dopamine D4 receptor biogenesis
Kathleen Van Craenenbroeck1, Stewart D Clark, Michael J Cox
1Laboratory of Molecular Neurobiology, Center for Addiction and Mental Health, Toronto, Ontario M5T 1R8, Canada.
The Journal of Biological Chemistry
|March 10, 2005
Summary
Antipsychotics act as pharmacological chaperones, up-regulating dopamine receptor expression by stabilizing receptors and reducing degradation. This chaperone effect, also seen with dopamine, varies between dopamine receptor D4 (DRD4) variants, impacting receptor biogenesis.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Dopamine receptors, particularly the D2 class (DRD2, DRD3, DRD4), are crucial for neurological functions and are targets for antipsychotic drugs.
- The dopamine receptor D4 (DRD4) gene exhibits high polymorphism, with specific variants linked to attention deficit hyperactivity disorder.
- Receptor folding efficiency is a critical factor in dopamine receptor biogenesis and function.
Purpose of the Study:
- To investigate the role of antipsychotics as pharmacological chaperones for dopamine receptors, using DRD4 as a model.
- To explore the mechanism of chaperone-mediated up-regulation, including effects on receptor degradation and folding.
- To determine if dopamine itself can act as a chaperone and if DRD4 variants exhibit differential responses.
Main Methods:
- Utilized DRD4 as a model system to study antipsychotic and dopamine chaperone effects.
- Assessed receptor expression levels and folding mutant rescue in response to pharmacological treatments.
- Investigated the involvement of the 26 S proteasome pathway in receptor degradation.
- Examined the influence of the dopamine transporter on dopamine's chaperone activity.
Main Results:
- Antipsychotics function as potent pharmacological chaperones, increasing DRD4 expression and rescuing folding mutants.
- Chaperone-mediated up-regulation involves decreased degradation via the 26 S proteasome, likely through stabilization in the endoplasmic reticulum.
- Dopamine, when transported into cells, also acts as a chaperone for DRD4.
- Different DRD4 repeat variants show varying sensitivity to the chaperone effect.
Conclusions:
- Receptor folding efficiency is a rate-limiting step in dopamine receptor biogenesis, with variations among receptor variants.
- Antipsychotics and dopamine can act as pharmacological chaperones, influencing receptor expression and potentially contributing to their clinical effects.
- The chaperone activity of dopaminergic ligands may represent a significant aspect of their therapeutic profile.