RGD Reference Report - PSD-95 expression controls L-DOPA dyskinesia through dopamine D1 receptor trafficking. - Rat Genome Database

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PSD-95 expression controls L-DOPA dyskinesia through dopamine D1 receptor trafficking.

Authors: Porras, G  Berthet, A  Dehay, B  Li, Q  Ladepeche, L  Normand, E  Dovero, S  Martinez, A  Doudnikoff, E  Martin-Negrier, ML  Chuan, Q  Bloch, B  Choquet, D  Boue-Grabot, E  Groc, L  Bezard, E 
Citation: Porras G, etal., J Clin Invest. 2012 Nov 1;122(11):3977-89. doi: 10.1172/JCI59426. Epub 2012 Oct 8.
RGD ID: 7248595
Pubmed: PMID:23041629   (View Abstract at PubMed)
PMCID: PMC3484432   (View Article at PubMed Central)
DOI: DOI:10.1172/JCI59426   (Journal Full-text)

L-DOPA-induced dyskinesia (LID), a detrimental consequence of dopamine replacement therapy for Parkinson's disease, is associated with an alteration in dopamine D1 receptor (D1R) and glutamate receptor interactions. We hypothesized that the synaptic scaffolding protein PSD-95 plays a pivotal role in this process, as it interacts with D1R, regulates its trafficking and function, and is overexpressed in LID. Here, we demonstrate in rat and macaque models that disrupting the interaction between D1R and PSD-95 in the striatum reduces LID development and severity. Single quantum dot imaging revealed that this benefit was achieved primarily by destabilizing D1R localization, via increased lateral diffusion followed by increased internalization and diminished surface expression. These findings indicate that altering D1R trafficking via synapse-associated scaffolding proteins may be useful in the treatment of dyskinesia in Parkinson's patients.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Parkinson's disease treatmentISODrd1 (Rattus norvegicus)7248595; 7248595 RGD 
Parkinson's disease treatmentIDA 7248595 RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
D1 dopamine receptor binding  IPIDrd1 (Rattus norvegicus)7248595 RGD 
protein binding  IPIDlg4 (Rattus norvegicus)7248595 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Dlg4  (discs large MAGUK scaffold protein 4)
Drd1  (dopamine receptor D1)

Genes (Mus musculus)
Drd1  (dopamine receptor D1)

Genes (Homo sapiens)
DRD1  (dopamine receptor D1)


Additional Information