Folding efficiency is rate-limiting in dopamine D4 receptor biogenesis.
Dopamine receptors are G protein-coupled receptors that are critically involved in locomotion, reward, and cognitive processes. The D2 class of dopamine receptors (DRD2, -3, and -4) is the target for antipsychotic medication. DRD4 has been implicated in cognition, and genetic studies have found an association between a highly polymorphic repeat sequence in the human DRD4 coding region and attention deficit hyperactivity disorder. Using DRD4 as a model, we show that antipsychotics can function as potent pharmacological chaperones up-regulating receptor expression and can also rescue a non-functional DRD4 folding mutant. This chaperone-mediated up-regulation involves reduced degradation by the 26 S proteasome; likely via the stabilization of newly synthesized receptor in the endoplasmic reticulum. Dopamine itself can function as a chaperone when shuttled into the cell by means of the dopamine transporter. Furthermore, different repeat variants of DRD4 display differential sensitivity to this chaperone effect. These data suggest that folding efficiency may be rate-limiting for dopamine receptor biogenesis and that this efficiency differs between receptor variants. Consequently, the clinical profile of dopaminergic ligands, including antipsychotics, may include their ability to serve as pharmacological chaperones.
Van Craenenbroeck
Kathleen
K
Laboratory of Molecular Neurobiology, Center for Addiction and Mental Health, Toronto, Ontario M5T 1R8, Canada.
Clark
Stewart D
SD
Cox
Michael J
MJ
Oak
James N
JN
Liu
Fang
F
Van Tol
Hubert H M
HH
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D015152:Blotting, Northern; D015153:Blotting, Western; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D004247:DNA / Q000737:chemistry; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D008024:Ligands; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D018832:Molecular Chaperones / Q000737:chemistry; D009154:Mutation; D011110:Polymorphism, Genetic; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014176:Protein Biosynthesis; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D017448:Receptors, Dopamine D2 / Q000737:chemistry*; D050638:Receptors, Dopamine D4; D013997:Time Factors; D014158:Transcription, Genetic; D015854:Up-Regulation
D014150:Antipsychotic Agents; C493599:DRD4 protein, human; D008024:Ligands; D018832:Molecular Chaperones; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4; D004247:DNA; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D004298:Dopamine