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Naloxone-precipitated morphine withdrawal syndrome in wild-type and Rgs4 null mice. Data are expressed as means Ϯ standard errors of the means. Black stars, morphine- versus saline-treated animals of the same genotype; white stars, wild-type versus mutant groups receiving the same treatment (two-tailed Student t test). One star, P Ͻ 0.05; two stars, P Ͻ 0.01.
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RGS proteins are negative regulators of signaling through heterotrimeric G protein-coupled receptors and, as such, are in
a position to regulate a plethora of biological phenomena. However, those have just begun to be explored in vivo. Here, we
describe a mouse line deficient for Rgs4, a gene normally expressed early on in discrete populations of d...
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... shown). At later stages of development and in the adult, Rgs4 is switched on in many telencephalic and diencephalic structures. The gross histological structure of the brain, the pattern of lacZ expression, and Nissl and Golgi stains on the cortex of heterozygous and homozygous mutants failed to reveal any difference between them ( Fig. 3E and E’ and data not shown). signaling. Endogenous or exogenous RGS proteins have been shown in vitro to dampen signaling through the -opioid receptor (9, 37, 38). It follows that Rgs4 could regulate antino- ciception by endogenous or exogenous opioids, both presyn- aptically in nociceptor neurons of the dorsal root ganglia and postsynaptically in second-order sensory neurons on which they project, two sites of strong Rgs4 expression (13, 17) (Fig. 2E). We therefore tested the sensitivity of wt mice and mutants first to pain and then to the analgesic effects of morphine treatment. Mutant mice had normal pain sensitivity in the tail flick test and showed first-reaction latency comparable to that of wt mice in the hot-plate test (Table 2). In the shock threshold test, subtle differences between wt mice and mutants were detected: the shock levels at which mice first detected the shock (flinch) were comparable in wt and Rgs4 lacZ/lacZ mice (Table 2), but the shock intensity required to induce jumping was significantly increased in Rgs4 lacZ/lacZ mice compared to wt ( t 21 ϭ 2.76; P Ͻ 0.05, Student t test) (Table 2). Thus, the proportion of mutants displaying a jumping reaction before the cutoff point (41.6%) was significantly reduced compared to wt mice (90.9%) ( 2 ϭ 6.1; P Ͻ 0.05), suggesting an effect of the mutation on central processing of painful stimuli. Systemic injection of morphine at the dose of 8 mg/kg induced comparable antinociceptive effects in wt mice and mutants in the tail flick assay [treatment effect, F(1,19) ϭ 12.9 (numbers in parentheses represent degrees of freedom corresponding to each experiment) and P Ͻ 0.01; genotype effect, F(1,19) ϭ 0.2 and P Ͼ 0.05; genotype ϫ treatment interaction, F(1,19) ϭ 0.6 and P Ͼ 0.05] as well as in the first reaction to the hot-plate test [treatment effect, F(1,19) ϭ 17.5 and P Ͻ 0.001; genotype effect, F(1,19) ϭ 0.4 and P Ͼ 0.05; genotype ϫ treatment interaction, F(1,19) ϭ 0.4 and P Ͼ 0.05]. Another potential role of Rgs4 connected to its biochemical capacity to regulate opioid signaling is suggested by its expression in the LC (16, 17). The LC, the main noradrenergic center of the brain, has a high level of opioid receptors and is hypoth- esized on numerous grounds to be a mediator of the opioid withdrawal syndrome (reviewed in reference 31), although the evidence has been extensively questioned (reviewed in references 8 and 46). We therefore tested a role for Rgs4 in somatic signs of abstinence to opioids according to the procedure described in reference 4 (see Materials and Methods). No difference between mutants and wt mice was found, except for an almost complete suppression of the sniffing reflex (Fig. 4). It is of note that sniffing, a minor sign of abstinence, also stood out in the D2 dopamine receptor knockout mice as being the only withdrawal symptom affected (exacerbated, in that case) (27). These data stand in stark contrast with the marked increase in morphine-induced analgesia and physical symptoms of withdrawal in Rgs9 - 2 knockout mice (49). The difference could be due to class-specific effects (RGS9, belonging to the C class of RGS proteins, possesses, unlike RGS4, DEP and GGL domains) or to tissue distribution differences (the site[s] of Rgs9 - 2 action on analgesia or withdrawal being presently unknown). Future studies should aim at exploring morphine tolerance (delayed in Rgs9 knockouts [49]) and unraveling either more subtle or more integrative aspects of responses to pain in Rgs4 mutants. No defect in prepulse inhibition in Rgs4 mutant mice. Along a different line of research, significant association between the Rgs4 locus and schizophrenia has been reported in several studies (5, 7, 30, 47), and Rgs4 transcripts have been found to be reduced in cortices of schizophrenic patients (28; see reference 18 for a review). The consequent status of Rgs4 as a susceptibility gene for schizophrenia is strengthened by its abundant expression in the cortex, where it could regulate dopaminergic and glutamatergic transmission, both invoked in models of schizophrenia (see references 18 and 23 for a review). We therefore tested mutant mice for PPI, a measure of sensorimotor gating abilities, whose decrease is one of the most widely accepted schizophrenia-related behaviors in rodents (see reference 14 for a review). Mutant mice displayed a normal startle response compared to wt mice at all tested acoustic stimulus intensities (Fig. 5A). They also showed a normal PPI across all prepulse intensities used (Fig. 5B). Another test of schizophrenia-like cognitive dysfunction in rodents (latent inhibition) should be performed in the future, as well as potential interactions of the Rgs4 null mutation with schizophrenogenic environmental paradigms (45). We also tested for depression- and anxiety-related symptoms (by the tail suspension test and the open-field test, respectively) and for associative learning and working memory defects (by Pavlovian fear conditioning and Y-maze spontaneous alternation, respectively). Rgs4 lacZ/lacZ mice did not show any difference in their performance compared to wt mice in any of these tests (not shown). In conclusion, subtle positive symptoms in Rgs4 mutants (namely, lower weight, partially penetrant, genetic back- ground-dependent early lethality, poorer sensorimotor coordination, and central integration of painful stimuli) point to developmental and physiological roles for Rgs4 . Further puri- fication of the genetic background may unmask other, presum- ably subtler, behavioral phenotypes by reducing the variability between individuals. On the other hand, combined inactivation of other Rgs genes, facilitated by the fertility of Rgs4 null mice, may reveal roles hitherto masked by redundancy. Finally, post- natal inactivation allowed by our conditional knockout scheme could unveil roles developmentally compensated for in Rgs4 null ...
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The involvement of reactive oxygen species (ROS) in morphine-induced analgesia and tolerance has been suggested, yet how and where ROS take part in these processes remains largely unknown. Here, we report a novel role for the superoxide-generating enzyme NOX1/NADPH oxidase in the regulation of analgesia and acute analgesic tolerance. In mice lackin...
Citations
... Interestingly, Rgs4 is also regulated by Stau2 ( [19], criteria 2). The mRNA of Rgs4 encodes a GTPase-activating protein of the G protein-coupled receptor (GPCR) pathway important for synaptic function ( [28,29], criteria 3). Several members of this pathway including Rgs4, Calm3 and Gna11 are bound by Stau2 ( Figure 1D) [19]. ...
RNA-binding proteins (RBPs) act as posttranscriptional regulators controlling the fate of target mRNAs. Unraveling how RNAs are recognized by RBPs and in turn are assembled into neuronal RNA granules is therefore key to understanding the underlying mechanism. While RNA sequence elements have been extensively characterized, the functional impact of RNA secondary structures is only recently being explored. Here, we show that Staufen2 binds complex, long-ranged RNA hairpins in the 3′-untranslated region (UTR) of its targets. These structures are involved in the assembly of Staufen2 into RNA granules. Furthermore, we provide direct evidence that a defined Rgs4 RNA duplex regulates Staufen2-dependent RNA localization to distal dendrites. Importantly, disrupting the RNA hairpin impairs the observed effects. Finally, we show that these secondary structures differently affect protein expression in neurons. In conclusion, our data reveal the importance of RNA secondary structure in regulating RNA granule assembly, localization and eventually translation. It is therefore tempting to speculate that secondary structures represent an important code for cells to control the intracellular fate of their mRNAs.
... RGS4 belongs to the R4/B subfamily and the mammalian form is shown to be expressed in developing nervous system and adult brain [19][20][21] . Several studies point to a role for RGS4 in modulating different neuronal signaling such as dopaminergic, serotonergic, noradrenergic, glutamatergic and opioid [22][23][24] . Rgs4 is considered a strong candidate susceptibility gene for schizophrenia and a strong decrease of its mRNA and proteins levels have been described in postmortem samples of schizophrenia patients [25][26][27] . ...
... Xenopus, mice and zebrafish studies have shown abundant expression of rgs4 in developing nervous system such as neural folds, central and peripheral neuronal precursors 20,28,29 . However, Rgs4 knockout mice showed normal neuronal development 24 whereas zebrafish morphants also showed normal neuronal development but led to motility defects that could be rescued by activating Akt signaling 28 . Indeed, Rgs4 activity has been linked, mainly through in vitro studies, to several signaling cascades such as the PI3K/Akt, MEK/Erk and the mechanistic regulator of rapamacycin, mTOR with conflicting outcomes 28,[30][31][32] . ...
... It is important to note that Rgs4 is a positive regulator of Akt activity during development. Another interesting observation is the requirement of Rgs4 in regulating neuronal numbers in zebrafish while its activity is dispensable for mice neurogenesis 24 . This raises the possibility of a significant redundancy with other RGS in mice that compensates the lack of RGS4. ...
The Regulator of G protein signaling 4 (Rgs4) is a member of the RGS proteins superfamily that modulates the activity of G-protein coupled receptors. It is mainly expressed in the nervous system and is linked to several neuronal signaling pathways; however, its role in neural development in vivo remains inconclusive. Here, we generated and characterized a rgs4 loss of function model (MZrgs4) in zebrafish. MZrgs4 embryos showed motility defects and presented reduced head and eye sizes, reflecting defective motoneurons axon outgrowth and a significant decrease in the number of neurons in the central and peripheral nervous system. Forcing the expression of Rgs4 specifically within motoneurons rescued their early defective outgrowth in MZrgs4 embryos, indicating an autonomous role for Rgs4 in motoneurons. We also analyzed the role of Akt, Erk and mechanistic target of rapamycin (mTOR) signaling cascades and showed a requirement for these pathways in motoneurons axon outgrowth and neuronal development. Drawing on pharmacological and rescue experiments in MZrgs4, we provide evidence that Rgs4 facilitates signaling mediated by Akt, Erk and mTOR in order to drive axon outgrowth in motoneurons and regulate neuronal numbers.
... morphine in the tail withdrawal test compared to control given scrambled antisense (Garzón et al., 2001). In contrast, constitutive RGS4 knockout mice do not display alterations in pain sensitivity in tests of acute nociception (Grillet et al., 2005). This finding may be due to redundancy of RGS action. ...
Opioid drugs are the gold standard for the management of pain, but their use is severely limited by dangerous and unpleasant side effects. All clinically available opioid analgesics bind to and activate the mu-opioid receptor (MOR), a heterotrimeric G-protein-coupled receptor, to produce analgesia. The activity of these receptors is modulated by a family of intracellular RGS proteins or regulators of G-protein signaling proteins, characterized by the presence of a conserved RGS Homology (RH) domain. These proteins act as negative regulators of G-protein signaling by serving as GTPase accelerating proteins or GAPS to switch off signaling by both the Gα and βγ subunits of heterotrimeric G-proteins. Consequently, knockdown or knockout of RGS protein activity enhances signaling downstream of MOR. In this review we discuss current knowledge of how this activity, across the different families of RGS proteins, modulates MOR activity, as well as activity of other members of the opioid receptor family, and so pain and analgesia in animal models, with particular emphasis on RGS4 and RGS9 families. We discuss inhibition of RGS proteins with small molecule inhibitors that bind to sensitive cysteine moieties in the RH domain and the potential for targeting this family of intracellular proteins as adjuncts to provide an opioid sparing effect or as standalone analgesics by promoting the activity of endogenous opioid peptides. Overall, we conclude that RGS proteins may be a novel drug target to provide analgesia with reduced opioid-like side effects, but that much basic work is needed to define the roles for specific RGS proteins, particularly in chronic pain, as well as a need to develop newer inhibitors.
... MO (rgs4/Rgs4 cRNA) -locomotion defects, aberrant development of axons; no changes in the number of neurons; the rgs4-related axonogenesis mediated by Akt signaling (Cheng et al., 2013) -abnormal neuronal differentiation in Rgs4 knockout mice (Grillet et al., 2005) decrease in the level of RGS4 mRNA and protein (Levitt et al., 2006) K. Gawel, et al. Neuroscience and Biobehavioral Reviews 107 (2019) 6-22 open field, place preference and novel diving tank) in adult fish, if/how disruption of dopamine signalling in early-life stages affects the adult behavioural phenotype. ...
Schizophrenia is a mental disorder that affects 1% of the population worldwide and is manifested as a broad spectrum of symptoms, from hallucinations to memory impairment. It is believed that genetic and/or environmental factors may contribute to the occurrence of this disease. Recently, the zebrafish has emerged as a valuable and attractive model for various neurological disorders including schizophrenia. In this review, we describe current pharmacological models of schizophrenia with special emphasis on providing insights into the pros and cons of using zebrafish as a behavioural model of this disease. Moreover, we highlight the advantages and utility of using zebrafish for elucidating the genetic mechanisms underlying this psychiatric disorder. We believe that the zebrafish has high potential also in the area of precision medicine and may complement the development of therapeutics, especially for pharmacoresistant patients.
... However, such changes could not be found in other related studies [9,10]. Additionally, the behavioral studies in RGS4 knockout mice failed to show any differences in schizophrenia-like behavior [11]. This may be due to developmental adaptations and genetic compensation for RGS4 in the knockout mice, thereby masking the establishment of a clear phenotype. ...
... It has been demonstrated that RGS4 knockout mice had subtle sensorimotor deficits, but the other behavioral parameters did not support schizophrenia-like behaviors [11]. However, gene knockout mouse models carrying constitutive mutations were often associated with several disadvantages such as genetic compensation and developmental adaptations that could mask a clear phenotype. ...
Rationale: Although molecular investigations of regulator of G-protein signaling 4 (RGS4) alterations in schizophrenia patients yielded partially inconsistent findings, the previous studies suggested that RGS4 is both a positional and functional candidate gene for schizophrenia and is significantly decreased in the prefrontal cortex. However, the exact role of RGS4 in the pathophysiology of schizophrenia is unclear. Moreover, a whole genome transcription profile study showed the possibility of RGS4-regulated expression of SLC7A11(xCT), a component of cysteine/glutamate transporter or system xc⁻. We hypothesized that system xc⁻ is a therapeutic target of RGS4 deficit-mediated schizophrenia.
Methods: Pharmacological and genetic manipulation of RGS4 in organotypic brain slice cultures were used as an ex vivo model to investigate its role in system xc⁻ and glutamatergic function. Lentiviral-based mouse models with RGS4 deficit in the prefrontal cortex and treatment with system xc⁻ activator, N-acetyl cysteine (NAC), were utilized to observe their impacts on glutamatergic function and schizophrenic behaviors.
Results: Genetic and pharmacological inhibition of RGS4 resulted in a significant decrease in SLC7A11 (xCT) expression and hypofunction of system xc⁻ and reduced glutamatergic function in organotypic brain slice cultures. However, NAC restored the dysregulation of RGS4-mediated functional deficits of glutamate. Moreover, knockdown of RGS4 specifically in the prefrontal cortex caused mice to exhibit behaviors related to schizophrenia such as increased stereotypy, impaired prepulse inhibition, deficits in social interactions, working memory, and nesting behavior, while enhancing sensitivity to the locomotor stimulatory effect of MK-801. These mice displayed glutamatergic dysfunction in the prefrontal cortex, which may have contributed to the behavioral deficits. RGS4 knockdown mice that received NAC treatment had improved glutamatergic dysfunction and schizophrenia behaviors.
Conclusion: Our results suggest that RGS4 deficit induces dysregulation and dysfunction of system xc⁻, which further results in functional deficits of the glutamatergic system and subsequently to schizophrenia-related behavioral phenotypes. Activation of system xc⁻ offers a promising strategy to treat RGS4 deficit-mediated schizophrenia.
... RGS4 has been associated with the development of schizophrenia (Chowdari et al., 2002). GPCR signalling is generally implicated in amyloid-b processing (Thathiah et al., 2009) and targeting GPCRs has been suggested as a possible therapeutic pathway; however, Rgs4 knockout mice did not have any deficits in associative learning or working memory (Grillet et al., 2005), so it may be that knockdown of RGS4 is not the best GPCR pathway target and GNA12 may be a more viable alternative. In the peptide dataset, CCT5 was counted in two KRONOSII modules and COMT was counted in five RUSH modules. ...
Our hypothesis is that changes in gene and protein expression are crucial to the development of late-onset Alzheimer's disease. Previously we examined how DNA alleles control downstream expression of RNA transcripts and how those relationships are changed in late-onset Alzheimer's disease. We have now examined how proteins are incorporated into networks in two separate series and evaluated our outputs in two different cell lines. Our pipeline included the following steps: (i) predicting expression quantitative trait loci; (ii) determining differential expression; (iii) analysing networks of transcript and peptide relationships; and (iv) validating effects in two separate cell lines. We performed all our analysis in two separate brain series to validate effects. Our two series included 345 samples in the first set (177 controls, 168 cases; age range 65-105; 58% female; KRONOSII cohort) and 409 samples in the replicate set (153 controls, 141 cases, 115 mild cognitive impairment; age range 66-107; 63% female; RUSH cohort). Our top target is heat shock protein family A member 2 (HSPA2), which was identified as a key driver in our two datasets. HSPA2 was validated in two cell lines, with overexpression driving further elevation of amyloid-β40 and amyloid-β42 levels in APP mutant cells, as well as significant elevation of microtubule associated protein tau and phosphorylated-tau in a modified neuroglioma line. This work further demonstrates that studying changes in gene and protein expression is crucial to understanding late onset disease and further nominates HSPA2 as a specific key regulator of late-onset Alzheimer's disease processes.10.1093/brain/awy215_video1awy215media15824729224001.
... The regulators of the G-protein signaling (RGS) family have important roles in the modulation of GPCR-mediated signaling pathways through the interaction of G protein subunits with various effectors (Bilodeau and Schwendt, 2016;Levitt et al., 2006). RGS4 is widely distributed throughout brain regions such as the prefrontal cortex, hippocampus, locus coeruleus, and striatum (Grillet et al., 2005). In particular, several studies have shown the modulatory function of RGS4 on various GPCRs including the muscarinic and dopamine receptors (Ding et al., 2006;Taymans et al., 2003) as well as on changes in accumbal RGS4 expression following morphine treatment (Han et al., 2010). ...
Crosstalk between G-protein signaling and glutamatergic transmission within the brain reward circuits is critical for long-term emotional effects (depression and anxiety), cravings, and negative withdrawal symptoms associated with opioid addiction. A previous study showed that Regulator of G-protein signaling 4 (RGS4) may be implicated in opiate action in the nucleus accumbens (NAc). However, the mechanism of the NAc-specific RGS4 actions that induce the behavioral responses to opiates remains largely unknown. The present study used a short hairpin RNA (shRNA)-mediated knock-down of RGS4 in the NAc of the mouse brain to investigate the relationship between the activation of ionotropic glutamate receptors and RGS4 in the NAc during morphine reward. Additionally, the shRNA-mediated RGS4 knock-down was implemented in NAc/striatal primary-cultured neurons to investigate the role that striatal neurons have in the morphine- induced activation of ionotropic glutamate receptors. The results of this study show that the NAc-specific knockdown of RGS4 significantly increased the behaviors associated with morphine and did so by phosphorylation of the GluR1 (Ser831) and NR2A (Tyr1325) glutamate receptors in the NAc. Furthermore, the knock-down of RGS4 enhanced the phosphorylation of the GluR1 and NR2A glutamate receptors in the primary NAc/striatal neurons during spontaneous morphine withdrawal. These findings show a novel molecular mechanism of RGS4 in glutamatergic transmission that underlies the negative symptoms associated with morphine administration.
... In another study using NIH-3T3 mouse preadipocyte cells, RGS2 overexpression promoted adipogensis in the presence of a ligand for PPAR γ [52]. RGS4 knockout mice also showed a significantly lower body weight compared to wild type mice [53], though in a separate study, these mice showed no significant effect on body weight but had increased circulating free fatty acid, indicating a role in lipolysis [54]. The role of RGS2 or RGS4 in human adipogenesis however remains unknown. ...
... To distinguish the two different scenarios would require additional future study to effectively overexpress RGS4 during adipogenic differentiation. Nevertheless, our observation of the positive role that RGS4 plays during adipogenesis is consistent with past study of RGS4 knockout mice, which showed a significantly lower body weight compared to wild type mice [53], though in a separate study, the observed weight difference was contributed to increased catecholamine secretion in adrenal gland and consequently lipolysis in adipose tissue [54]. ...
Background:
Understanding the molecular basis underlying the formation of bone-forming osteocytes and lipid-storing adipocytes will help provide insights into the cause of disorders originating in stem/progenitor cells and develop therapeutic treatments for bone- or adipose-related diseases. In this study, the role of RGS2 and RGS4, two members of the regulators of G protein signaling (RGS) family, was investigated during adipogenenic and osteogenenic differentiation of human mesenchymal stem cells (hMSCs).
Results:
Expression of RGS2 and RGS4 were found to be inversely regulated during adipogenesis induced by dexamethasone (DEX) and 3-isobutyl-methylxanthine, regardless if insulin was present, with RGS2 up-regulated and RGS4 down-regulated in response to adipogenic induction. RGS2 expression was also up-regulated during osteogenesis at a level similar to that induced by treatment of DEX alone, a shared component of adipogenic and osteogenic differentiation inducing media, but significantly lower than the level induced by adipogenic inducing media. RGS4 expression was down-regulated during the first 48 h of osteogenesis but up-regulated afterwards, in both cases at levels similar to that induced by DEX alone. Expression knock-down using small interfering RNA against RGS2 resulted in decreased differentiation efficiency during both adipogenesis and osteogenesis. On the other hand, expression knock-down of RGS4 also resulted in decreased adipogenic differentiation but increased osteogenic differentiation.
Conclusions:
RGS2 and RGS4 are differentially regulated during adipogenic and osteogenic differentiation of hMSCs. In addition, both RGS2 and RGS4 play positive roles during adipogenesis but opposing roles during osteogenesis, with RGS2 as a positive regulator and RGS4 as a negative regulator. These results imply that members of RGS proteins may play multifaceted roles during human adipogenesis and osteogenesis to balance or counterbalance each other's function during those processes.
... RGS4 up-regulation, together with a DRD2 reduction, in transcript numbers seems to be further evidence of DOPA-signaling alteration. Interestingly, recent studies have suggested direct RGS4 inhibition as a new target for Parkinson's care [42,43]. ...
Chlorpyrifos (CPF) is an organophosphate insecticide used to control pests on a variety of food and feed crops. In mammals, maternal exposure to CPF has been reported to induce cerebral cortex thinning, alteration of long-term brain cognitive function, and Parkinson-like symptoms, but the mechanisms of these processes are not fully understood. In this study, we aimed to gain a deeper understanding of the alterations induced in the brains of mice chronically exposed to CPF by dietary intake. For our purpose, we analysed F1 offspring (sacrificed at 3 and 8 months) of Mus musculus, treated in utero and postnatally with 3 different doses of CPF (0.1-1-10 mg/kg/day). Using RT2 Profiler PCR Arrays, we evaluated the alterations in the expression of 84 genes associated with neurodegenerative diseases. In the brains of exposed mice, we evidenced a clear dose–response relationship for AChE inhibition and alterations of gene expression. Some of the genes that were steadily down-regulated, such as Pink1, Park 2, Sv2b, Gabbr2, Sept5 and Atxn2, were directly related to Parkinson’s onset. Our experimental results shed light on the possibility that long-term CPF exposure may exert membrane signalling alterations which make brain cells more susceptible to develop neurodegenerative diseases.
Keywords
... For example, RGS2 protein deficient mice have shown promise as models for investi (1) Exaggerated vasoconstriction and increased systemic blood pressure are attributed to prolonged GqPCR-dependent signaling and reduced cGMP-mediated vasodilation [35,36] (2) GqPCR signaling in response to cardiac pressure overload (i.e. transverse aortic constriction, TAC) is enhanced, causing cardiac hypertrophy and early mortality; cGMP hydrolytic enzyme PDE5 inhibition with sildenafil blunts TAC-mediated cardiac hypertrophy in RGS2 +/+ mice (Control), whereas antihypertrophy effect of PDE5 inhibition is suppressed in RGS2-/-animal [34] (3) Excessive M3 muscarinic receptor activity occurs and induces severe atrial tachycardia/fibrillation [65] RGS4 P ulmonary hypertension/ventricular hypertrophy/ cardiomyopathy Cardiac-specific RGS4 overexpression Knockout R GS4 protein expression is upregulated and serves as a compensatory regulator to prevent heart failure from further progression [37][38][39][40][41][42] Left ventricular hypertrophy is delayed in response to pressure overload [53] M2 muscarinic receptor-mediated bradycardia is augmented [66] RGS5 Hypertension/atherosclerosis Overexpression Knockout (1) ...
PURPOSE The superfamily of G protein-coupled receptors (GPCR) are activated by biological molecules (e.g. neurotransmitters) and are involved in many physiological events. As exaggerated GPCR-mediated signaling may contribute to cardiovascular disorders, RGS proteins (regulators of G-protein signaling) are viewed as an important regulatory molecule for the negative modulation of this signaling pathway. To address the significance of RGS proteins and suggest potential effects of exercise training on this molecule, a literature review on RGS proteins was conducted. METHODS A systemic search in PUBMED was performed to obtain previous studies investigating roles of RGS proteins in the cardiovascular systems. RESULTS RGS proteins directly bind to the Gα subunit of heterotrimeric G proteins to inhibit GPCR signaling pathways and terminate their activity. Using mice genetically lacking RGS2 and RGS5, these proteins have been shown to contribute to pressure overload-induced cardiac remodeling. Further, it has been suggested that systemic knockout of RGS2 protein causes hypertension by potentiating G protein signaling-mediated vascular responses and impairing nitric oxide/cGMP-induced vasorelaxation. Thus, RGS proteins have been suggested as potential drug targets for cardiovascular disorders accompanied by dysregulation of RGS proteins and GPCR signaling. Although exercise training has also been well-documented to strengthen cardiovascular function and ameliorate circulatory diseases, cellular mechanisms underlying the contribution of exercise intervention to RGS-mediated GPCR signaling have not been explored. CONCLUSIONS This brief review discusses roles played by RGS proteins in the cardiovascular system and suggests future studies for investigating the interaction between exercise training and RGS protein-mediated regulation of GPCR signaling.
