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
News
Research News
Conference News
Plain English
Forums
Current Hypotheses
Idea Lab
Online Discussions
Virtual Conferences
Interviews
Resources
What We Know
SchizophreniaGene
Animal Models
Drugs in Trials
Research Tools
Grants
Jobs
Conferences
Journals
Community Calendar
General Information
Community
Member Directory
Researcher Profiles
Institutes and Labs
About the Site
Mission
History
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
5HT and Glutamate Receptors—Unique Complex Linked to Psychosis

6 March 2008. A complex between two very different neurotransmitter receptors, a serotonin receptor and a metabotropic glutamate receptor, might help elucidate the underlying pathology of schizophrenia, according to an advance online publication in the February 24 Nature. Researchers led by Stuart Sealfon and Javier González-Maeso at Mount Sinai School of Medicine, New York, report that the metabotropic glutamate receptor 2 (mGluR2)/5-hydroxytryptamine 2A receptor (2AR) complex elicits unique cellular responses when activated by hallucinogenic drugs, which mimic some of the symptoms of schizophrenia, and that the expression of these receptors is altered in the brains of people with the disorder. The findings lead the authors to conclude that “…this complex is therefore a promising new target for the treatment of psychosis.”

That the 2AR and mGluR2 proteins interact is not such a far-fetched idea since both are G-protein-coupled receptors (GPCRs), which are known to form heterodimers and even larger mixed oligomers. However, all such complexes found to date are between GPCRs of the same class (there are six classes in all). What is unique about the 2AR/mGluR2 complex is that the receptors belong to different GPCR classes, and the researchers provide convincing evidence for this unique arrangement.

First author González-Maeso and colleagues discovered the complex when studying the distribution of metabotropic glutamate receptors. They found that the 2AR receptor rarely colocalized with mGluR3 in the sensory cortex of mice, but interestingly, cells containing 2AR almost always test positive for the mGluR2 subunit. When they investigated further, they found that 2AR was essential for proper expression of mGluR2 in cortical cells—mice with disrupted 2AR expression showed reduced mGluR2 levels.

Given that the receptors turn up in the same place and seem to have a regulatory relationship, the researchers wondered if they might form a complex. González-Maeso and colleagues used a variety of methods to put that theory to the test. Using immunoprecipitation of human cortical samples and transfected cells, as well as two techniques that reveal if molecules are in close molecular proximity (bioluminescence resonance energy transfer and fluorescence resonance energy transfer), the researchers conclude that the proteins do form a complex.

But would such an entity be functional? The answer to that question appears to be yes, since the affinity of one receptor appears to depend on the other. For example, when the researchers used the non-hydrolyzable GTP analog GTP-γS to drive the receptors apart, affinities of each for their ligands dropped. Also, the glutamate receptor agonist LY379268 increased the affinity of 2AR for the hallucinogenic agents DOI, DOM, and DOB, whereas the hallucinogen DOI decreased the affinity of mGluR2 for its agonists. The researchers were able to abolish these allosteric interactions by using receptor antagonists.

Interestingly, the authors found that the mere presence of mGluR2 influences 2AR function by decreasing activation of the Gαq/11 subunit and increasing activation of the inhibitor Gαi subunit—these are components of G-protein signaling. These effects were reversed in the presence of mGluR2 agonists. Furthermore, glutamate agonists seem to modulate the effects of hallucinogens on 2AR receptor signaling in mice. Hallucinogens such as LSD can trigger two types of signaling through 2AR, one involving activation of the transcription factor c-fos and the other activating the transcription factor egr-2. Non-hallucinogenic 2AR agonists only activate c-fos. The researchers found that the glutamate agonist LY379268 had no effect on the c-fos pathway, but blocked the induction of egr-2, suggesting that the agonist specifically blocks only the hallucinogenic signaling that is propagated through the 2AR receptor. In fact, they also found that LY379268 can block head twitching movements in mice induced by hallucinogenic drugs. “Our results are consistent with the hypothesis that the 2AR-mGluR2 complex integrates serotonin and glutamate signaling to regulate the sensory gating functions of the cortex, a process that is disrupted in psychosis,” write the authors.

These findings offer new support for the idea that metabotropic glutamate receptor agonists may prove beneficial in schizophrenia. Glutamate signaling is reduced in the disorder and recent clinical trials suggest that mGluR agonists may be compensatory (see SRF related news story). There are indications, too, that mGluRs have an active role in learning and memory, which suggests that mGluR agonists may have the added benefit of correcting cognitive impairment associated with the disease (see SRF related news story). Now, González-Maeso and colleagues’ findings suggest that mGluR agonists could have an effect on hallucinations. In fact, when they examined postmortem brain samples from schizophrenia patients, the researchers found that the levels of 2AR and mGluR2 are increased and decreased, respectively, in membranes from the cortex. “Thus, the increased 2AR and decreased mGluR2 found in the brain in schizophrenia may predispose to a hallucinogenic pattern of signaling,” suggest the authors.—Tom Fagan.

Reference:
Gonzalez-Maeso J, Ang RL, Yuen T, Chan P, Weisstaub NV, Lopez-Gimenez, JF, Zhou M, Okawa Y Callado LF, Milligan G, Gingrich JA, Filizola M, Meana JJ, Sealfon SC. Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature. 2008 Feb 24; [Epub ahead of print] Abstract

 
Comments on News and Primary Papers
Comment by:  Brian Dean
Submitted 20 March 2008 Posted 20 March 2008

Altered receptor dimerization: a new paradigm in the pathology of schizophrenia
Understanding the pathology of complex diseases such as schizophrenia requires the use of the full arsenal at the disposal of medical research. Such an approach has been used to make an exciting new discovery that suggests that abnormal dimerization between the serotonin 2A receptor (2AR) and the metabotropic glutamate 2 receptor(mGluR2) may underlie some of the symptoms of schizophrenia (González-Maeso et al., 2008).

This discovery is based on an initial finding that 2AR is coexpressed with mGluR2 in layer 5 of the mouse somatosensory cortex (SCx) and that levels of mGluR2 were decreased in the cortex of 2AR-/- mice, suggesting a relationship between the expression of the two genes. This hypothesis was further supported by data showing that expression of mGluR2 was selectively restored in mice where 2AR expression had been re-established in layer 5 of the SCx. From these data, and data from other studies suggesting G protein-coupled...  Read more


View all comments by Brian Dean

Comment by:  Gerard J. Marek (Disclosure)
Submitted 21 March 2008 Posted 21 March 2008

Another bicycle trip?
Ever since dopamine was first implicated in the therapeutic effects of antipsychotic drugs by Arvid Carlsson and colleagues over 50 years ago, and then dopamine D2 receptors were implicated in the Parkinsonian side effects and late-evolving movement disorders, an intense search has been underway for antipsychotic drugs that might act through other mechanisms. In parallel with this search, drugs with psychotomimetic effects in healthy volunteers or exacerbating psychosis have also been used to discover new antipsychotic drugs. With an evolving understanding of the neuropharmacology underlying ketamine or PCP, amphetamines, and serotonergic hallucinogens (LSD, mescaline, and psilocybin), glutamatergic, dopaminergic, and serotonergic theories of psychotic pathophysiology have been advanced. Converging evidence points to activation of 5-HT2A receptors as a necessary action in the psychotomimetic effects of the serotonergic “hallucinogens.” The recent description of a proof-of-concept clinical study where a prodrug for a metabotropic glutamate2/3...  Read more


View all comments by Gerard J. Marek
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  
Affiliation  
Country or Territory  
*Login Email Address  
*Confirm Email Address  
*Password  
*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.

Comment:

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

References:


SRF News
SRF Comments
Text Size
Reset Text Size
Email this pageEmail this page

Share/Bookmark
Copyright © 2005- 2014 Schizophrenia Research Forum Privacy Policy Disclaimer Disclosure Copyright