Allelic Variation in<i>RGS4</i>Impacts Functional and Structural Connectivity in the Human Brain

Buckholtz, Joshua W.; Meyer‐Lindenberg, Andreas; Honea, Robyn A.; Straub, Richard E.; Pezawas, Lukas; Egan, Michael; Vakkalanka, Radhakrishna; Kolachana, Bhaskar; Verchinski, Beth A.; Sust, Steven; Mattay, Venkata S.; Weinberger, Daniel R.; Callicott, Joseph H.

doi:10.1523/jneurosci.5112-06.2007

Cited by 100 publications

(67 citation statements)

References 101 publications

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“…Although, to the best of our knowledge, this is the first GxE study showing evidence of the interplay between psychosocial stress and RGS4 genetic variation on PEs, neurobiological research has indicated that the RGS4 gene, because of its function and biological properties, may be a relevant candidate gene for psychotic outcomes 25. RGS4 is highly expressed in important brain regions involved in the pathophysiology of schizophrenia (e.g., PFC) and, importantly, it also shows an increased responsiveness to environmental stimuli, can modulate the function of G‐protein‐coupled neurotransmitter receptors critically implicated in schizophrenia‐related disorders 53, 54.…”

Section: Discussionmentioning

confidence: 86%

“…However, differential effects of COMT Val158Met alleles have been found in non‐clinical and clinical samples 14, 22, 23, 24. Other candidate genes related with dopamine signaling that have been associated previously with PEs, such as the regulator of G‐protein signaling 4 25, 26, 27, are also of interest for exploring their possible involvement in the development of such experiences through a stress‐reactivity pathway. The oxytocin receptor gene ( OXTR ) is another promising candidate for understanding individual differences in the response of the dopaminergic and stress‐response systems.…”

Section: Introductionmentioning

confidence: 99%

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The role of stress‐regulation genes in moderating the association of stress and daily‐life psychotic experiences

Cristóbal-Narváez

Sheinbaum

Myin-Germeys

et al. 2017

Acta Psychiatr Scand

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ObjectiveThe interaction of single nucleotide polymorphisms with both distal and proximal environmental factors across the extended psychosis phenotype is understudied. This study examined (i) the interaction of relevant SNPs with both early‐life adversity and proximal (momentary) stress on psychotic experiences (PEs) in an extended psychosis sample; and (ii) differences between early‐psychosis and non‐clinical groups for these interactions.MethodsTwo hundred and forty‐two non‐clinical and 96 early‐psychosis participants were prompted randomly eight times daily for 1 week to complete assessments of current experiences, including PEs and stress. Participants also reported on childhood trauma and were genotyped for 10 SNPs on COMT, RGS4, BDNF, FKBP5, and OXTR genes.ResultsUnlike genetic variants, distal and proximal stressors were associated with PEs in both samples and were more strongly associated with PEs in the early‐psychosis than in the non‐clinical group. The RGS4 TA and FKBP5 CATT haplotypes interacted with distal stress, whereas the A allele of OXTR (rs2254298) interacted with proximal stress, increasing momentary levels of PEs in the early‐psychosis group. No interactions emerged with COMT or BDNF variants.ConclusionIndividual differences in relevant stress‐regulation systems interact with both distal and proximal psychosocial stressors in shaping the daily‐life manifestation of PEs across the psychosis continuum.

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Section: Discussionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

The role of stress‐regulation genes in moderating the association of stress and daily‐life psychotic experiences

Cristóbal-Narváez

Sheinbaum

Myin-Germeys

et al. 2017

Acta Psychiatr Scand

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“…Rgs4 is generally thought to be a negative modulator of Gα subunits by promoting their hydrolysis of GTP and by antagonizing the regulation of their effectors, although the actions of Rgs proteins are more complex, because they can either inhibit or facilitate several actions of their associated receptors (10,11). Preclinical and clinical studies link Rgs4 dysfunction to hypertension, cardiac hypertrophy, schizophrenia, Parkinson disease, and drug addiction, among other disorders (11)(12)(13)(14)(15). In the brain, Rgs4 is expressed in high abundance in prefrontal cortex (PFC) and is also present at high levels in regions associated with stress and depression, including nucleus accumbens (NAc), locus coeruleus, hippocampus, and several other limbic brain regions (16,17).…”

mentioning

confidence: 99%

Regulator of G protein signaling 4 is a crucial modulator of antidepressant drug action in depression and neuropathic pain models

Stratinaki

Varidaki

Mitsi

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Regulator of G protein signaling 4 (Rgs4) is a signal transduction protein that controls the function of monoamine, opiate, muscarinic, and other G protein-coupled receptors via interactions with Gα subunits. Rgs4 is expressed in several brain regions involved in mood, movement, cognition, and addiction and is regulated by psychotropic drugs, stress, and corticosteroids. In this study, we use genetic mouse models and viral-mediated gene transfer to examine the role of Rgs4 in the actions of antidepressant medications. We first analyzed human postmortem brain tissue and found robust up-regulation of RGS4 expression in the nucleus accumbens (NAc) of subjects receiving standard antidepressant medications that target monoamine systems. Behavioral studies of mice lacking Rgs4 , including specific knockdowns in NAc, demonstrate that Rgs4 in this brain region acts as a positive modulator of the antidepressant-like and antiallodynic-like actions of several monoamine-directed antidepressant drugs, including tricyclic antidepressants, selective serotonin reuptake inhibitors, and norepinephrine reuptake inhibitors. Studies using viral-mediated increases in Rgs4 activity in NAc further support this hypothesis. Interestingly, in prefrontal cortex, Rgs4 acts as a negative modulator of the actions of nonmonoamine-directed drugs that are purported to act as antidepressants: the N-methyl-D-aspartate glutamate receptor antagonist ketamine and the delta opioid agonist (+)-4-[(αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide. Together, these data reveal a unique modulatory role of Rgs4 in the brain region-specific actions of a wide range of antidepressant drugs and indicate that pharmacological interventions at the level of RGS4 activity may enhance the actions of such drugs used for the treatment of depression and neuropathic pain.

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“…RGS4 is linked to various pathologies, including Parkinson disease (54) and schizophrenia (55). It might be assumed that the function of RGS4 in such pathological processes would be attributed to its attenuation of G␣ i/o -or G␣ q -mediated G protein-coupled receptor signaling, functioning as a GTPase-activating protein (3) or effector antagonist (4), respectively.…”

Section: Discussionmentioning

confidence: 99%

A Novel Mechanism Involving Coordinated Regulation of Nuclear Levels and Acetylation of NF-YA and Bcl6 Activates RGS4 Transcription

Yang

Huang

Chatterjee

et al. 2010

Journal of Biological Chemistry

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Neuronally enriched RGS4 plays a critical role attenuating G protein signaling in brain, although the mechanisms regulating RGS4 expression are unknown. Here we describe a novel mechanism for transcriptional activation of RGS4 in neuron-like PC6 cells, where RGS4 is markedly induced during confluence-induced growth arrest. Transcriptional activation of RGS4 in confluent PC6 cells was accompanied by impaired G i/o -dependent MAPK activation. In the human RGS4 gene promoter, we identified three phylogenetically conserved cis-elements: an inverted CCAAT box element (ICE), a cAMP response element, and a B-cell lymphoma 6 (Bcl6)-binding site. The ICE and the cAMP response element mediate activation, and the Bcl6 site mediates repression of RGS4 transcription. Activation of RGS4 transcription in confluent PC6 cells is accompanied by increases in NF-YA and C/EBP␤ and decreases in Bcl6 levels in the nucleus. Increases in NF-YA and C/EBP␤ lead to their increased binding to the RGS4 promoter in vivo, and dominant negative forms of these proteins repressed RGS4 promoter activity. Acetylation of NF-YA and Bcl6 were increased in postconfluent cells. Trichostatin A stimulation of RGS4 promoter activity, accompanied by increased binding of NF-YA and decreased binding of Bcl6 to the promoter, was abolished by mutation of the ICE and enhanced by mutation of the Bcl6 site. These findings demonstrate a dynamic and coordinated regulation of nuclear levels and acetylation status of trans-acting factors critical in determining the off/on state of the RGS4 promoter. Regulator of G protein signaling 4 (RGS4)2 is a member of the mammalian RGS family of proteins of which 30 members exist in humans. RGS proteins were discovered as essential negative regulators of heterotrimeric G protein signaling by genetic studies in yeast and Caenorhabditis elegans (1, 2). These proteins act as GTPase-activating proteins for heterotrimeric G ␣ subunits (3), thereby accelerating the shut-off mechanism for G protein signaling. Some RGS proteins, including RGS4, can also act as effector antagonists (4, 5) or can directly or indirectly interact with G protein-coupled receptors (6 -8), actions that contribute to their negative regulatory effects on G protein signaling in cells.Although G protein signaling is involved in virtually every known physiological process and RGS proteins are an important component of this signaling, the mechanisms regulating expression of RGS genes are largely unknown. Studies have shown that several RGS genes are induced under certain physiological conditions, for example RGS1 during mitogenic activation of lymphocytes (9), RGS2 in the early stage of 3T3-L1 differentiation to adipocytes (10), RGS16 during genotoxic stress (11), and the yeast RGS gene SST2 by pheromone (12). Regulation of RGS4 expression has also been noted in facial motoneuronal precursors during embryonic development in mice (13), in epithelial and endothelial cells during tubulogenesis (14), and in rat PC12 cells during cell confluence (15). In the study by Gril...

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Allelic Variation inRGS4Impacts Functional and Structural Connectivity in the Human Brain

Cited by 100 publications

References 101 publications

The role of stress‐regulation genes in moderating the association of stress and daily‐life psychotic experiences

The role of stress‐regulation genes in moderating the association of stress and daily‐life psychotic experiences

Regulator of G protein signaling 4 is a crucial modulator of antidepressant drug action in depression and neuropathic pain models

A Novel Mechanism Involving Coordinated Regulation of Nuclear Levels and Acetylation of NF-YA and Bcl6 Activates RGS4 Transcription

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