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D₂ Dopamine Receptors Colocalize Regulator of G-Protein Signaling 9-2 (RGS9-2) via the RGS9 DEP Domain, and RGS9 Knock-Out Mice Develop Dyskinesias Associated with Dopamine Pathways

Kovoor, Abraham and Seyffarth, Petra and Ebert, Jana and Barghshoon, Sami and Chen, Ching-Kang and Schwarz, Sigrid and Axelrod, Jeffrey D. and Cheyette, Benjamin N. R. and Simon, Melvin I. and Lester, Henry A. and Schwarz, Johannes (2005) D₂ Dopamine Receptors Colocalize Regulator of G-Protein Signaling 9-2 (RGS9-2) via the RGS9 DEP Domain, and RGS9 Knock-Out Mice Develop Dyskinesias Associated with Dopamine Pathways. Journal of Neuroscience, 25 (8). pp. 2157-2165. ISSN 0270-6474. PMCID PMC6726050. https://resolver.caltech.edu/CaltechAUTHORS:20200506-074200832

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Abstract

Regulator of G-protein signaling 9-2 (RGS9-2), a member of the RGS family of Gα GTPase accelerating proteins, is expressed specifically in the striatum, which participates in antipsychotic-induced tardive dyskinesia and in levodopa-induced dyskinesia. We report that RGS9 knock-out mice develop abnormal involuntary movements when inhibition of dopaminergic transmission is followed by activation of D₂-like dopamine receptors (DRs). These abnormal movements resemble drug-induced dyskinesia more closely than other rodent models. Recordings from striatal neurons of these mice establish that activation of D₂-like DRs abnormally inhibits glutamate-elicited currents. We show that RGS9-2, via its DEP domain (for Disheveled, EGL-10, Pleckstrin homology), colocalizes with D₂DRs when coexpressed in mammalian cells. Recordings from oocytes coexpressing D₂DR or the m2 muscarinic receptor and G-protein-gated inward rectifier potassium channels show that RGS9-2, via its DEP domain, preferentially accelerates the termination of D₂DR signals. Thus, alterations in RGS9-2 may be a key factor in the pathway leading from D₂DRs to the side effects associated with the treatment both of psychoses and Parkinson's disease.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1523/jneurosci.2840-04.2005DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726050PubMed CentralArticle
ORCID:
AuthorORCID
Lester, Henry A.0000-0002-5470-5255
Additional Information:© 2005 Society for Neuroscience. Received Jan. 15, 2004; revised Jan. 4, 2005; accepted Jan. 4, 2005. This work was supported by grants from the Interdisziplinäres Zentrum für klinische Forschung Leipzig (TP C19), National Institutes of Health (GM-29836, GM05982, MH001750, and MH-49176), and by a National Research Service Award to A.K. (MH019552).
Funders:
Funding AgencyGrant Number
Interdisziplinäres Zentrum für klinische Forschung LeipzigTP C19
NIHGM-29836
NIHGM05982
NIHMH001750
NIHMH-49176
NIHMH019552
Subject Keywords:antipsychotic; D2 dopamine receptor; dyskinesia; DEP domain; RGS9; striatum
Issue or Number:8
PubMed Central ID:PMC6726050
Record Number:CaltechAUTHORS:20200506-074200832
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200506-074200832
Official Citation:D2 Dopamine Receptors Colocalize Regulator of G-Protein Signaling 9-2 (RGS9-2) via the RGS9 DEP Domain, and RGS9 Knock-Out Mice Develop Dyskinesias Associated with Dopamine Pathways. Abraham Kovoor, Petra Seyffarth, Jana Ebert, Sami Barghshoon, Ching-Kang Chen, Sigrid Schwarz, Jeffrey D. Axelrod, Benjamin N. R. Cheyette, Melvin I. Simon, Henry A. Lester, Johannes Schwarz. Journal of Neuroscience 23 February 2005, 25 (8) 2157-2165; DOI: 10.1523/JNEUROSCI.2840-04.2005
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:103015
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:06 May 2020 16:14
Last Modified:06 May 2020 16:14

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