Browse
Submit Data
Databases
API
Help

Dataset Information

14 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Adaptive gene regulation in the Striatum of RGS9-deficient mice.

ABSTRACT:

Background

RGS9-deficient mice show drug-induced dyskinesia but normal locomotor activity under unchallenged conditions.

Results

Genes related to Ca2+ signaling and their functions were regulated in RGS9-deficient mice.

Conclusion

Changes in Ca2+ signaling that compensate for RGS9 loss-of-function can explain the normal locomotor activity in RGS9-deficient mice under unchallenged conditions.

Significance

Identified signaling components may represent novel targets in antidyskinetic therapy. The long splice variant of the regulator of G-protein signaling 9 (RGS9-2) is enriched in striatal medium spiny neurons and dampens dopamine D2 receptor signaling. Lack of RGS9-2 can promote while its overexpression prevents drug-induced dyskinesia. Other animal models of drug-induced dyskinesia rather pointed towards overactivity of dopamine receptor-mediated signaling. To evaluate changes in signaling pathways mRNA expression levels were determined and compared in wild-type and RGS9-deficient mice. Unexpectedly, expression levels of dopamine receptors were unchanged in RGS9-deficient mice, while several genes related to Ca2+ signaling and long-term depression were differentially expressed when compared to wild type animals. Detailed investigations at the protein level revealed hyperphosphorylation of DARPP32 at Thr34 and of ERK1/2 in striata of RGS9-deficient mice. Whole cell patch clamp recordings showed that spontaneous synaptic events are increased (frequency and size) in RGS9-deficient mice while long-term depression is reduced in acute brain slices. These changes are compatible with a Ca2+-induced potentiation of dopamine receptor signaling which may contribute to the drug-induced dyskinesia in RGS9-deficient mice.

SUBMITTER: Busse K

PROVIDER: S-EPMC3963927 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Distribution of RGS9-2 in neurons of the mouse striatum.

Project description:Regulators of G protein signaling (RGS) proteins negatively modulate G protein-coupled receptor (GPCR) signaling activity by accelerating G protein hydrolysis of GTP, hastening pathway shutoff. A wealth of data from cell culture experiments using exogenously expressed proteins indicates that RGS9 and other RGS proteins have the potential to down-regulate a significant number of pathways. We have used an array of biochemical and tissue staining techniques to examine the subcellular localization and membrane binding characteristics of endogenous RGS9-2 and known binding partners in rodent striatum and tissue homogenates. A small fraction of RGS9-2 is present in the soluble cytoplasmic fraction, whereas the majority is present primarily associated with the plasma membrane and structures insoluble in non-ionic detergents that efficiently extract the vast majority of its binding partners, R7BP and G(beta5). It is specifically excluded from the cell nucleus in mouse striatal tissue. In cultured striatal neurons, RGS9-2 is found at extrasynaptic sites primarily along the dendritic shaft near the spine neck. Heterogeneity in RGS9-2 detergent solubility along with its unique subcellular localization suggests that its mechanism of membrane anchoring and localization is complex and likely involves additional proteins beside R7BP. An important nuclear function for RGS9-2 seems unlikely.

| S-EPMC3642247 | biostudies-literature

Dopamine D2 long receptor-deficient mice display alterations in striatum-dependent functions.

Project description:The dopamine D2 receptor (D2) system has been implicated in several neurological and psychiatric disorders, such as schizophrenia and Parkinson's disease. There are two isoforms of the D2 receptor: the long form (D2L) and the short form (D2S). The two isoforms are generated by alternative splicing of the same gene and differ only by 29 amino acids in their protein structures. Little is known about the distinct functions of either D2 isoform, primarily because selective pharmacological agents are not available. We generated D2L receptor-deficient (D2L-/-) mice by making a subtle mutation in the D2 gene. D2L-/- mice (which still express functional D2S) displayed reduced levels of locomotion and rearing behavior. Interestingly, haloperidol produced significantly less catalepsy and inhibition of locomotor activity in D2L-/- mice. These findings suggest that D2L and D2S may contribute differentially to the regulation of certain motor functions and to the induction of the extrapyramidal side effects associated with the use of typical antipsychotic drugs (e.g., haloperidol). Quinpirole induced a similar initial suppression of locomotor activity in both D2L-/- and wild-type mice. In addition, the D2S receptor in the mutant mice functioned approximately equally well as did D2L as an impulse-modulating autoreceptor. This suggests that the functions of these two isoforms are not dependent on the formation of receptor heterodimers. Our findings may provide novel information for potentially developing improved antipsychotic drugs.

| S-EPMC6773184 | biostudies-literature

Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice.

Project description:Parkinson's disease (PD) is characterized by the selective vulnerability of the nigrostriatal dopaminergic circuit. Recently, loss-of-function mutations in the PTEN-induced kinase 1 (PINK1) gene have been linked to early-onset PD. How PINK1 deficiency causes dopaminergic dysfunction and degeneration in PD patients is unknown. Here, we investigate the physiological role of PINK1 in the nigrostriatal dopaminergic circuit through the generation and multidisciplinary analysis of PINK1(-/-) mutant mice. We found that numbers of dopaminergic neurons and levels of striatal dopamine (DA) and DA receptors are unchanged in PINK1(-/-) mice. Amperometric recordings, however, revealed decreases in evoked DA release in striatal slices and reductions in the quantal size and release frequency of catecholamine in dissociated chromaffin cells. Intracellular recordings of striatal medium spiny neurons, the major dopaminergic target, showed specific impairments of corticostriatal long-term potentiation and long-term depression in PINK1(-/-) mice. Consistent with a decrease in evoked DA release, these striatal plasticity impairments could be rescued by either DA receptor agonists or agents that increase DA release, such as amphetamine or l-dopa. These results reveal a critical role for PINK1 in DA release and striatal synaptic plasticity in the nigrostriatal circuit and suggest that altered dopaminergic physiology may be a pathogenic precursor to nigrostriatal degeneration.

| S-EPMC1890561 | biostudies-literature

Cloning and characterization of RGS9-2: a striatal-enriched alternatively spliced product of the RGS9 gene.

Project description:Regulators of G-protein signaling (RGS) proteins act as GTPase-activating proteins (GAPs) for alpha subunits of heterotrimeric G-proteins. Previous in situ hybridization analysis of mRNAs encoding RGS3-RGS11 revealed region-specific expression patterns in rat brain. RGS9 showed a particularly striking pattern of almost exclusive enrichment in striatum. In a parallel study, RGS9 cDNA, here referred to as RGS9-1, was cloned from retinal cDNA libraries, and the encoded protein was identified as a GAP for transducin (Galphat) in rod outer segments. In the present study we identify a novel splice variant of RGS9, RGS9-2, cloned from a mouse forebrain cDNA library, which encodes a striatal-specific isoform of the protein. RGS9-2 is 191 amino acids longer than the retinal isoform, has a unique 3' untranslated region, and is highly enriched in striatum, with much lower levels seen in other brain regions and no expression detectable in retina. Immunohistochemistry showed that RGS9-2 protein is restricted to striatal neuropil and absent in striatal terminal fields. The functional activity of RGS9-2 is supported by the finding that it, but not RGS9-1, dampens the Gi/o-coupled mu-opioid receptor response in vitro. Characterization of a bacterial artificial chromosome genomic clone of approximately 200 kb indicates that these isoforms represent alternatively spliced mRNAs from a single gene and that the RGS domain, conserved among all known RGS members, is encoded over three distinct exons. The distinct C-terminal domains of RGS9-2 and RGS9-1 presumably contribute to unique regulatory properties in the neural and retinal cells in which these proteins are selectively expressed.

| S-EPMC6782559 | biostudies-literature

A unique role of RGS9-2 in the striatum as a positive or negative regulator of opiate analgesia.

Project description:The signaling molecule RGS9-2 is a potent modulator of G-protein-coupled receptor function in striatum. Our earlier work revealed a critical role for RGS9-2 in the actions of the ?-opioid receptor (MOR) agonist morphine. In this study, we demonstrate that RGS9-2 may act as a positive or negative modulator of MOR-mediated behavioral responses in mice depending on the agonist administered. Paralleling these findings we use coimmunoprecipitation assays to show that the signaling complexes formed between RGS9-2 and G? subunits in striatum are determined by the MOR agonist, and we identify RGS9-2 containing complexes associated with analgesic tolerance. In striatum, MOR activation promotes the formation of complexes between RGS9-2 and several G? subunits, but morphine uniquely promotes an association between RGS9-2 and G?i3. In contrast, RGS9-2/G?q complexes assemble after acute application of several MOR agonists but not after morphine application. Repeated morphine administration leads to the formation of distinct complexes, which contain RGS9-2, G?5, and G?q. Finally, we use simple pharmacological manipulations to disrupt RGS9-2 complexes formed during repeated MOR activation to delay the development of analgesic tolerance to morphine. Our data provide a better understanding of the brain-region-specific signaling events associated with opiate analgesia and tolerance and point to pharmacological approaches that can be readily tested for improving chronic analgesic responsiveness.

| S-EPMC3412365 | biostudies-literature

Dissociation of Adaptive Thermogenesis from Glucose Homeostasis in Microbiome-Deficient Mice.

Project description:Recent studies suggest that a key mechanism whereby the gut microbiome influences energy balance and glucose homeostasis is through the recruitment of brown and beige adipocytes, primary mediators of the adaptive thermogenic response. To test this, we assessed energy expenditure and glucose metabolism in two complementary mouse models of gut microbial deficiency, which were exposed to a broad range of thermal and dietary stresses. Neither ablation of the gut microbiome, nor the substantial microbial perturbations induced by cold ambient temperatures, influenced energy expenditure during cold exposure or high-fat feeding. Nevertheless, we demonstrated a critical role for gut microbial metabolism in maintaining euglycemia through the production of amino acid metabolites that optimized hepatic TCA (tricarboxylic acid) cycle fluxes in support of gluconeogenesis. These results distinguish the dispensability of the gut microbiome for the regulation of energy expenditure from its critical contribution to the maintenance of glucose homeostasis.

| S-EPMC7888548 | biostudies-literature

R7BP complexes with RGS9-2 and RGS7 in the striatum differentially control motor learning and locomotor responses to cocaine.

Project description:In the striatum, signaling through G protein-coupled dopamine receptors mediates motor and reward behavior, and underlies the effects of addictive drugs. The extent of receptor responses is determined by RGS9-2/Gbeta5 complexes, a striatally enriched regulator that limits the lifetime of activated G proteins. Recent studies suggest that the function of RGS9-2/Gbeta5 is controlled by the association with an additional subunit, R7BP, making elucidation of its contribution to striatal signaling essential for understanding molecular mechanisms of behaviors mediated by the striatum. In this study, we report that elimination of R7BP in mice results in motor coordination deficits and greater locomotor response to morphine administration, consistent with the essential role of R7BP in maintaining RGS9-2 expression in the striatum. However, in contrast to previously reported observations with RGS9-2 knockouts, mice lacking R7BP do not show higher sensitivity to locomotor-stimulating effects of cocaine. Using a striatum-specific knockdown approach, we show that the sensitivity of motor stimulation to cocaine is instead dependent on RGS7, whose complex formation with R7BP is dictated by RGS9-2 expression. These results indicate that dopamine signaling in the striatum is controlled by concerted interplay between two RGS proteins, RGS7 and RGS9-2, which are balanced by a common subunit, R7BP.

| S-EPMC2887292 | biostudies-literature

Increased novelty-induced locomotion, sensitivity to amphetamine, and extracellular dopamine in striatum of Zdhhc15-deficient mice.

Project description:Novelty-seeking behaviors and impulsivity are personality traits associated with several psychiatric illnesses including attention deficits hyperactivity disorders. The underlying neural mechanisms remain poorly understood. We produced and characterized a line of knockout mice for zdhhc15, which encodes a neural palmitoyltransferase. Genetic defects of zdhhc15 were implicated in intellectual disability and behavioral anomalies in humans. Zdhhc15-KO mice showed normal spatial learning and working memory but exhibited a significant increase in novelty-induced locomotion in open field. Striatal dopamine content was reduced but extracellular dopamine levels were increased during the habituation phase to a novel environment. Administration of amphetamine and methylphenidate resulted in a significant increase in locomotion and extracellular dopamine levels in the ventral striatum of mutant mice compared to controls. Number and projections of dopaminergic neurons in the nigrostriatal and mesolimbic pathways were normal. No significant change in the basal palmitoylation of known ZDHHC15 substrates including DAT was detected in striatum of zdhhc15 KO mice using an acyl-biotin exchange assay. These results support that a transient, reversible, and novelty-induced elevation of extracellular dopamine in ventral striatum contributes to novelty-seeking behaviors in rodents and implicate ZDHHC15-mediated palmitoylation as a novel regulatory mechanism of dopamine in the striatum.

| S-EPMC7813841 | biostudies-literature

Fluoxetine Potentiates Oral Methylphenidate-Induced Gene Regulation in the Rat Striatum.

Project description:Methylphenidate (MP) is combined with selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (FLX) to treat various disorders. MP, a dopamine reuptake inhibitor, helps manage attention-deficit hyperactivity disorder (ADHD) and is abused as a cognitive enhancer; it has a reduced addiction liability. We showed that combining FLX (serotonin) with MP potentiates MP-induced gene regulation in the striatum. These studies used intraperitoneal drug administration, which is relevant for MP abuse. Clinically, MP and FLX are taken orally (slower bioavailability). Here, we investigated whether chronic oral administration of MP and FLX also altered striatal gene regulation. MP (30/60 mg/kg/day), FLX (20 mg/kg/day), and MP + FLX were administered in rats' drinking water for 8 h/day over 4 weeks. We assessed the expression of dynorphin and substance P (both markers for striatal direct pathway neurons) and enkephalin (indirect pathway) by in situ hybridization histochemistry. Chronic oral MP alone produced a tendency for increased dynorphin and substance P expression and no changes in enkephalin expression. Oral FLX alone did not increase gene expression. In contrast, when given together, FLX greatly enhanced MP-induced expression of dynorphin and substance P and to a lesser degree enkephalin. Thus, FLX potentiated oral MP-induced gene regulation predominantly in direct pathway neurons, mimicking cocaine effects. The three functional domains of the striatum were differentially affected. MP + SSRI concomitant therapies are indicated in ADHD/depression comorbidity and co-exposure occurs with MP misuse as a cognitive enhancer by patients on SSRIs. Our findings indicate that MP + SSRI combinations, even given orally, may enhance addiction-related gene regulation.

| S-EPMC8500935 | biostudies-literature

RGS9-2--controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states.

Project description:The striatal protein Regulator of G-protein signaling 9-2 (RGS9-2) plays a key modulatory role in opioid, monoamine, and other G-protein-coupled receptor responses. Here, we use the murine spared-nerve injury model of neuropathic pain to investigate the mechanism by which RGS9-2 in the nucleus accumbens (NAc), a brain region involved in mood, reward, and motivation, modulates the actions of tricyclic antidepressants (TCAs). Prevention of RGS9-2 action in the NAc increases the efficacy of the TCA desipramine and dramatically accelerates its onset of action. By controlling the activation of effector molecules by G protein ? and ?? subunits, RGS9-2 affects several protein interactions, phosphoprotein levels, and the function of the epigenetic modifier histone deacetylase 5, which are important for TCA responsiveness. Furthermore, information from RNA-sequencing analysis reveals that RGS9-2 in the NAc affects the expression of many genes known to be involved in nociception, analgesia, and antidepressant drug actions. Our findings provide novel information on NAc-specific cellular mechanisms that mediate the actions of TCAs in neuropathic pain states.

| S-EPMC4568688 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data