Schizophrenia Research Forum - A Catalyst for Creative Thinking
Home Profile Membership/Get Newsletter Log In Contact Us
 For Patients & Families
What's New
Recent Updates
SRF Papers
Current Papers
Search All Papers
Search Comments
Research News
Conference News
Plain English
Current Hypotheses
Idea Lab
Online Discussions
Virtual Conferences
What We Know
Animal Models
Drugs in Trials
Research Tools
Community Calendar
General Information
Member Directory
Researcher Profiles
Institutes and Labs
About the Site
SRF Team
Advisory Board
Support Us
How to Cite
Fan (E)Mail
The Schizophrenia Research Forum web site is sponsored by the Brain and Behavior Research Foundation and was created with funding from the U.S. National Institute of Mental Health.
Research News
back to News Search
An Arrestin Development: Antipsychotic Drugs Hit Dopamine Signaling in New Way

14 October 2008. All of the antipsychotic medicines used to treat schizophrenia hit dopamine receptors, and specifically the D2R class of G protein-coupled receptors. But G proteins are not the only messengers mobilized by the receptor. D2R and GPCRs also signal via a pathway involving the scaffolding protein β-arrestin and the Akt/GSK kinase pathway. That alternative pathway may be a key to the actions of antipsychotic medicines, according to new work from the laboratory of Marc Caron at Duke University Medical Center, Durham, North Carolina. In a paper published in the September 3 issue of PNAS online, Caron and colleagues present evidence that the panel of antipsychotic drugs shows a wide range of abilities to inhibit G protein signaling. At the same time, they all potently block dopamine-stimulated β-arrestin 2 binding to the receptor. The results suggest that the arrestin pathway may be the clinically relevant target of these drugs, a finding that has obvious implications for testing and developing new compounds.

D2 receptors signal mainly through inhibitory G proteins that reduce cAMP production, but more recently, researchers identified a second pathway involving β-arrestin and the Akt/GSK3 kinase cascade. Akt has been independently implicated in schizophrenia (see SRF related news story), and some reports suggest that GSK3 is regulated by antipsychotic drugs (Alimohamad et al., 2005; Li et al., 2007). The mood stabilizing drug lithium appears to modulate a β-arrestin/Akt signaling complex (see SRF related news story).

To ask how antipsychotic drugs affected the two arms of dopamine receptor signaling, first author Bernard Masri used a fluorescence energy transfer assay to measure either cAMP production or β-arrestin association in HEK cells expressing the long version of the D2R. For both measures, he used a BRET technique (bioluminescent fluorescence energy transfer, see SRF related news story). By attaching a bioluminescent tag (luciferase) to the dopamine receptor, and a reporter fluorophore (yellow fluorescent protein) to β-arrestin, Masri could measure the association of the two proteins in living cells. A similar BRET assay was used to measure cAMP levels in the cells.

In all, the investigators tested nine drugs from all classes of antipsychotics. All of the antipsychotics but one (aripiprazole) had intrinsic activity to stimulate cAMP accumulation, but none affected β-arrestin 2 association. In the presence of the dopamine receptor agonist quinpirole, the antipsychotics showed widely differing potencies as antagonists of cAMP inhibition. Most were active in sub-nanomolar range, but three (clozapine, desmethylclozapine, and quetiapine) had activity only at much higher (μM) concentrations, and never fully reversed the inhibition of cAMP production. In contrast, all of the agents inhibited quinpirole-stimulated β-arrestin recruitment at nM concentrations, and inhibited it completely.

“There seems to be a clear difference between the potencies of antipsychotics to antagonize these two signaling paradigms allowing them to discriminate one pathway versus the other,” the authors conclude. “Ultimately, it would be interesting to explore whether the efficacies of these compounds as antipsychotics and their relative liability for extrapyramidal side effects, correlate with their profile for either of these pathways.”

Dissecting the two pathways with new compounds appears feasible for GPCRs generally: a differential inhibition of signaling pathways by receptor-targeted compounds was recently observed for serotonin receptor agonists (see SRF related news story).—Pat McCaffrey.

Masri B, Salahpour A, Didriksen M, Ghisi V, Beaulieu JM, Gainetdinov RR, Caron MG. Antagonism of dopamine D2 receptor/beta-arrestin 2 interaction is a common property of clinically effective antipsychotics. Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13656-61. Epub 2008 Sep 3. Abstract

Comments on News and Primary Papers
Comment by:  Zachary Z. FreybergEneko UrizarHolly MooreJeffrey Lieberman (SRF Advisor)
Jonathan Javitch
Submitted 30 December 2008 Posted 30 December 2008

Reevaluation of the dopamine D2 receptor in...  Read more

View all comments by Zachary Z. Freyberg
View all comments by Eneko Urizar
View all comments by Holly Moore
View all comments by Jeffrey Lieberman
View all comments by Jonathan Javitch
Submit a Comment on this News Article
Make a comment on this news article. 

If you already are a member, please login.
Not sure if you are a member? Search our member database.

*First Name  
*Last Name  
Country or Territory  
*Login Email Address  
*Confirm Email Address  
*Confirm Password  
Remember my Login and Password?  
Get SRF newsletter with recent commentary?  
Enter the code as it is shown below:
This code helps prevent automated registrations.

I recommend the Primary Papers

Please note: A member needs to be both registered and logged in to submit a comment.


(If coauthors exist for this comment, please enter their names and email addresses at the end of the comment.)


SRF News
SRF Comments
Text Size
Reset Text Size
Copyright © 2005- 2016 Schizophrenia Research Forum Privacy Policy Disclaimer Disclosure Copyright