Journal article
Regulator of G-protein signaling 6 (RGS6) promotes anxiety and depression by attenuating serotonin-mediated activation of the 5-HT1A receptor-adenylyl cyclase axis
The FASEB journal, Vol.28(4), pp.1735-1744
04/2014
DOI: 10.1096/fj.13-235648
PMCID: PMC3963013
PMID: 24421401
Abstract
Targeting serotonin (5-HT) bioavailability with selective 5-HT reuptake inhibitors (SSRIs) remains the most widely used treatment for mood disorders. However, their limited efficacy, delayed onset of action, and side effects restrict their clinical utility. Endogenous regulator of G-protein signaling (RGS) proteins have been implicated as key inhibitors of 5-HT
1A
Rs, whose activation is believed to underlie the beneficial effects of SSRIs, but the identity of the specific RGS proteins involved remains unknown. We identify RGS6 as the critical negative regulator of 5-HT
1A
R-dependent antidepressant actions. RGS6 is enriched in hippocampal and cortical neurons, 5-HT
1A
R-expressing cells implicated in mood disorders.
RGS6
−/−
mice exhibit spontaneous anxiolytic and antidepressant behavior rapidly and completely reversibly by 5-HT
1A
R blockade. Effects of the SSRI fluvoxamine and 5-HT
1A
R agonist 8-OH-DPAT were also potentiated in
RGS6
+/−
mice. The phenotype of
RGS6
−/−
mice was associated with decreased CREB phosphorylation in the hippocampus and cortex, implicating enhanced Gα
i
-dependent adenylyl cyclase inhibition as a possible causative factor in the behavior observed in
RGS6
−/−
animals. Our results demonstrate that by inhibiting serotonergic innervation of the cortical-limbic neuronal circuit, RGS6 exerts powerful anxiogenic and prodepressant actions. These findings indicate that RGS6 inhibition may represent a viable means to treat mood disorders or enhance the efficacy of serotonergic agents.—Stewart, A., Maity, B., Wunsch, A. M., Meng, F., Wu, Q., Wemmie, J. A., Fisher, R. A. Regulator of G-protein signaling 6 (RGS6) promotes anxiety and depression by attenuating serotonin-mediated activation of the 5-HT
1A
receptor-adenylyl cyclase axis.
Details
- Title: Subtitle
- Regulator of G-protein signaling 6 (RGS6) promotes anxiety and depression by attenuating serotonin-mediated activation of the 5-HT1A receptor-adenylyl cyclase axis
- Creators
- Adele Stewart - Department of Pharmacology andBiswanath Maity - Department of Pharmacology andAmanda M Wunsch - Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA; andFantao Meng - Department of Pharmacology andQi Wu - Department of Pharmacology andJohn A Wemmie - Veterans Affairs Medical Center, Iowa City, Iowa, USARory A Fisher - Department of Pharmacology and
- Resource Type
- Journal article
- Publication Details
- The FASEB journal, Vol.28(4), pp.1735-1744
- DOI
- 10.1096/fj.13-235648
- PMID
- 24421401
- PMCID
- PMC3963013
- NLM abbreviation
- FASEB J
- ISSN
- 0892-6638
- eISSN
- 1530-6860
- Publisher
- Federation of American Societies for Experimental Biology; Bethesda, MD, USA
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health, award: CA‐161882; DOI: 10.13039/100000738, name: U.S. Department of Veterans Affairs; DOI: 10.13039/100000025, name: National Institute of Mental Health, award: 1R01MH085724‐01; DOI: 10.13039/100000050, name: National Heart, Lung, and Blood Institute, award: 5 R01 HL113863‐01
- Language
- English
- Date published
- 04/2014
- Academic Unit
- Molecular Physiology and Biophysics; Psychiatry; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Neurosurgery; Internal Medicine
- Record Identifier
- 9984003478102771
Metrics
18 Record Views