Making the Case for a Candidate Vulnerability Gene in Schizophrenia: Convergent Evidence for Regulator of G-Protein Signaling 4 (RGS4)

Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, Tennessee 37203, USA.
Biological Psychiatry (Impact Factor: 10.26). 10/2006; 60(6):534-7. DOI: 10.1016/j.biopsych.2006.04.028
Source: PubMed


Both genetic and environmental factors have been associated with an increased risk for schizophrenia. These factors are not mutually exclusive; a single gene can be a genetic factor (due to a mutation in the gene sequence) and a target of a physiological response to an environmental stimulus, both with the common endpoint of altered expression of the gene. Regulator of G-protein signaling 4 (RGS4) has been implicated as such a gene from three lines of evidence. First, a subset of genetic studies revealed an association between schizophrenia and non-functional polymorphisms in the RGS4 gene. Second, across the cortical mantle the expression of RGS4 mRNA is decreased in a diagnosis-specific manner in subjects with schizophrenia. Third, neurobiological studies demonstrate that RGS4 is highly responsive to environmental stimuli and capable of modulating the function of G-protein coupled neurotransmitter receptors implicated in schizophrenia. RGS4 is an example of a molecule that may underlie increased vulnerability through either genetic or non-genetic mechanisms, which we suggest may be typical of other genes in a complex, polygenic disorder such as schizophrenia.

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    • "Thus, breakdown in the functional segregation of these pathways might lead to aberrant modulation and dysregulation of cellular activity. Indeed, mutations in RGS4 have been linked to neuropsychiatric disorders such as schizophrenia (Levitt et al., 2006). Future studies are necessary to investigate the interactions of RGS4 and neuromodulatory signaling in disease. "
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    ABSTRACT: A diverse array of neuromodulators governs cellular function in the prefrontal cortex (PFC) via the activation of G-protein-coupled receptors (GPCRs). However, these functionally diverse signals are carried and amplified by a relatively small assortment of intracellular second messengers. Here, we examine whether two distinct Gαi-coupled neuromodulators (norepinephrine and GABA) act as redundant regulators of glutamatergic synaptic transmission. Our results reveal that, within single dendritic spines of layer 5 pyramidal neurons, alpha-2 adrenergic receptors (α2Rs) selectively inhibit excitatory transmission mediated by AMPA-type glutamate receptors, while type B GABA receptors (GABABRs) inhibit NMDA-type receptors. We show that both modulators act via the downregulation of cAMP and PKA. However, by restricting the lifetime of active Gαi, RGS4 promotes the independent control of these two distinct target proteins. Our findings highlight a mechanism by which neuromodulatory microdomains can be established in subcellular compartments such as dendritic spines. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 07/2015; 69(2). DOI:10.1016/j.celrep.2015.06.029 · 8.36 Impact Factor
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    • "Rgs4 is implicated in intestinal inflammation [6], [7], [59], [60], cardiovascular diseases [61]–[63] and psychiatric disorders [4], [8]–[12]. However, the regulatory mechanism of Rgs4 expression has not been well understood. "
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    ABSTRACT: Regulator of G-protein Signaling 4 (RGS4) plays an important role in regulating smooth muscle contraction, cardiac development, neural plasticity and psychiatric disorder. However, the underlying regulatory mechanisms remain elusive. Our recent studies have shown that upregulation of Rgs4 by interleukin (IL)-1β is mediated by the activation of NFκB signaling and modulated by extracellular signal-regulated kinases, p38 mitogen-activated protein kinase, and phosphoinositide-3 kinase. Here we investigate the effect of the c-Jun N-terminal kinase (JNK) pathway on Rgs4 expression in rabbit colonic smooth muscle cells. Cultured cells at first passage were treated with or without IL-1β (10 ng/ml) in the presence or absence of the selective JNK inhibitor (SP600125) or JNK small hairpin RNA (shRNA). The expression levels of Rgs4 mRNA and protein were determined by real-time RT-PCR and Western blot respectively. SP600125 or JNK shRNA increased Rgs4 expression in the absence or presence of IL-1β stimulation. Overexpression of MEKK1, the key upstream kinase of JNK, inhibited Rgs4 expression, which was reversed by co-expression of JNK shRNA or dominant-negative mutants for MKK4 or JNK. Both constitutive and inducible upregulation of Rgs4 expression by SP600125 was significantly inhibited by pretreatment with the transcription inhibitor, actinomycin D. Dual reporter assay showed that pretreatment with SP600125 sensitized the promoter activity of Rgs4 in response to IL-1β. Mutation of the AP1-binding site within Rgs4 promoter increased the promoter activity. Western blot analysis confirmed that IL-1β treatment increased the phosphorylation of JNK, ATF-2 and c-Jun. Gel shift and chromatin immunoprecipitation assays validated that IL-1β increased the in vitro and ex vivo binding activities of AP1 within rabbit Rgs4 promoter. Activation of MEKK1-MKK4-JNK-AP1 signal pathway plays a tonic inhibitory role in regulating Rgs4 transcription in rabbit colonic smooth muscle cells. This negative regulation may aid in maintaining the transient level of RGS4 expression.
    PLoS ONE 04/2012; 7(4):e35646. DOI:10.1371/journal.pone.0035646 · 3.23 Impact Factor
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    • "Schizophrenia is considered a neurodevelopmental disorder, with an important genetic component (Jones and Murray, 1991; Tsuang, 2000), as proven by a higher incidence among patients' first degree family members (McGuffin et al., 1995). Recent studies have stated the implication of several genes in the development of psychiatric disorders (Fatemi and Folsom, 2009), although there is no single genetic alteration that has been replicated in all studies (Levitt et al., 2006). On the other hand, many studies indicate that there must be other environmental factors that interact with genetic ones. "
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    ABSTRACT: Schizophrenia is a highly disabling and limiting disorder for patients and the possibility that infections by some microorganisms may be associated to its development may allow prevention and recovery. In the current study we have done a meta-analysis of studies that have assessed the possible association between detection of different infectious agents and schizophrenia. We report results that support the idea that there is a statistically significant association between schizophrenia and infection by Human Herpesvirus 2 (OR=1.34; CI 95%: 1.09-1.70; p=0.05), Borna Disease Virus (OR=2.03; CI 95%: 1.35-3.06; p<0.01), Human Endogenous Retrovirus W (OR=19.31; CI 95%: 6.74-55.29; p<0.001), Chlamydophila pneumoniae (OR=6.34; CI 95%: 2.83-14.19; p<0.001), Chlamydophila psittaci (OR=29.05; CI 95%: 8.91-94.70; p<0.001) and Toxoplasma gondii (OR=2.70; CI 95%: 1.34-4.42; p=0.005). The implications of these findings are discussed and further research options are also explicated.
    Schizophrenia Research 11/2011; 136(1-3):128-36. DOI:10.1016/j.schres.2011.10.026 · 3.92 Impact Factor
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