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1.
Mol Pharmacol ; 92(6): 630-639, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28954816

RESUMO

The adenosine A1 receptor (A1R) is a key mediator of the neuroprotective effect by endogenous adenosine. Yet targeting this receptor for neuroprotection is challenging due to its broad expression throughout the body. A mechanistic understanding of the regulation of A1R signaling is necessary for the future design of therapeutic agents that can selectively enhance A1R-mediated responses in the nervous system. In this study, we demonstrate that A1R activation leads to a sustained localization of regulator of G protein signaling 4 (RGS4) at the plasma membrane, a process that requires neurabin (a neural tissue-specific protein). A1R and RGS4 interact with the overlapping regions of neurabin. In addition, neurabin domains required for oligomerization are essential for formation of the A1R/neurabin/RGS4 ternary complex, as well as for stable localization of RGS4 at the plasma membrane and attenuation of A1R signaling. Thus, A1R and RGS4 each likely interact with one neurabin molecule in a neurabin homo-oligomer to form a ternary complex, representing a novel mode of regulation of G protein-coupled receptor signaling by scaffolding proteins. Our mechanistic analysis of neurabin-mediated regulation of A1R signaling in this study will be valuable for the future design of therapeutic agents that can selectively enhance A1R-mediated responses in the nervous system.


Assuntos
Proteínas dos Microfilamentos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Receptor A1 de Adenosina/metabolismo , Animais , Células COS , Membrana Celular/metabolismo , Chlorocebus aethiops , Células HEK293 , Humanos , Complexos Multiproteicos/metabolismo , Domínios Proteicos , Multimerização Proteica , Transporte Proteico , Proteínas RGS/metabolismo , Transdução de Sinais
2.
Proc Natl Acad Sci U S A ; 112(36): E5088-97, 2015 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-26305935

RESUMO

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 α and ßγ 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.


Assuntos
Antidepressivos/farmacologia , Corpo Estriado/metabolismo , Neuralgia/prevenção & controle , Proteínas RGS/metabolismo , Adaptação Fisiológica/efeitos dos fármacos , Adaptação Fisiológica/genética , Animais , Western Blotting , Corpo Estriado/fisiopatologia , Feminino , Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Redes Reguladoras de Genes/efeitos dos fármacos , Hiperalgesia/fisiopatologia , Hiperalgesia/prevenção & controle , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuralgia/genética , Neuralgia/fisiopatologia , Núcleo Accumbens/metabolismo , Núcleo Accumbens/fisiopatologia , Proteínas RGS/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Resultado do Tratamento
3.
Neurobiol Learn Mem ; 115: 43-8, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25150149

RESUMO

The signal transduction modulator Rgs9-2 (Regulator of G protein signaling 9-2) plays a key role in dopaminergic and opioidergic transmission in the striatum. Rgs9-2 is a potent modulator of opiate reward and analgesia, but its role in chronic pain remains unknown. Here, we use the spared nerve injury model (SNI), to evaluate the influence of Rgs9-2 in sensory symptoms, as well as in anxiety and depression-like behaviors observed under neuropathic pain conditions. Our data demonstrate that knockout of the Rgs9 gene reduces the intensity of thermal hyperalgesia and mechanical allodynia the first few days after nerve injury. This small, but significant effect is only observed at early time points after nerve injury, whereas after the first week of SNI, Rgs9 knockout (Rgs9KO) and Rgs9 wildtype (Rgs9WT) mice show similar levels of mechanical allodynia and thermal hyperalgesia. Furthermore, Rgs9-2 deletion exacerbates anxiety and depression like behaviors several weeks after the emergence of the neuropathic pain symptoms. Our findings also reveal a temporal and regional regulation of Rgs9-2 protein expression by neuropathic pain, as Rgs9-2 levels are reduced in the spinal cord a few days after nerve injury, whereas decreased Rgs9-2 levels in the Nucleus Accumbens (NAc) are only observed several weeks after nerve injury. Thus, adaptations in Rgs9-2 activity in the spinal cord and in the NAc may contribute to sensory and affective components of neuropathic pain.


Assuntos
Neuralgia/fisiopatologia , Proteínas RGS/fisiologia , Afeto/fisiologia , Animais , Ansiedade/fisiopatologia , Western Blotting , Depressão/fisiopatologia , Feminino , Hiperalgesia/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuralgia/psicologia , Núcleo Accumbens/química , Proteínas RGS/análise , Medula Espinal/química
4.
Neuropsychopharmacology ; 37(4): 1005-12, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22089315

RESUMO

The adaptor protein R7 family binding protein (R7BP) modulates G protein coupled receptor (GPCR) signaling and desensitization by controlling the function of regulator of G protein signaling (RGS) proteins. R7BP is expressed throughout the brain and appears to modulate the membrane localization and stability of three proteins that belong to R7 RGS family: RGS6, RGS7, and RGS9-2. RGS9-2 is a potent negative modulator of opiate and psychostimulant addiction and promotes the development of analgesic tolerance to morphine, whereas the role of RGS6 and RGS7 in addiction remains unknown. Recent studies revealed that functional deletion of R7BP reduces R7 protein activity by preventing their anchoring to the cell membrane and enhances GPCR responsiveness in the basal ganglia. Here, we take advantage of R7BP knockout mice in order to examine the way interventions in R7 proteins function throughout the brain affect opiate actions. Our results suggest that R7BP is a negative modulator of the analgesic and locomotor activating actions of morphine. We also report that R7BP contributes to the development of morphine tolerance. Finally, our data suggest that although prevention of R7BP actions enhances the analgesic responses to morphine, it does not affect the severity of somatic withdrawal signs. Our data suggest that interventions in R7BP actions enhance the analgesic effect of morphine and prevent tolerance, without affecting withdrawal, pointing to R7BP complexes as potential new targets for analgesic drugs.


Assuntos
Analgésicos Opioides/farmacologia , Tolerância a Medicamentos/fisiologia , Dependência de Morfina/metabolismo , Proteínas RGS/fisiologia , Síndrome de Abstinência a Substâncias/metabolismo , Animais , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Dependência de Morfina/genética , Dependência de Morfina/fisiopatologia , Proteínas RGS/deficiência , Proteínas RGS/genética , Síndrome de Abstinência a Substâncias/genética , Síndrome de Abstinência a Substâncias/fisiopatologia
5.
PLoS One ; 6(11): e27984, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22132185

RESUMO

Regulator of G protein signaling 9-2 (RGS9-2) is a protein that is highly enriched in the striatum, a brain region that mediates motivation, movement and reward responses. We identified a naturally occurring 5 nucleotide deletion polymorphism in the human RGS9 gene and found that the mean body mass index (BMI) of individuals with the deletion was significantly higher than those without. A splicing reporter minigene assay demonstrated that the deletion had the potential to significantly decrease the levels of correctly spliced RGS9 gene product. We measured the weights of rats after virally transduced overexpression of RGS9-2 or the structurally related RGS proteins, RGS7, or RGS11, in the nucleus accumbens (NAc) and observed a reduction in body weight after overexpression of RGS9-2 but not RGS7 or 11. Conversely, we found that the RGS9 knockout mice were heavier than their wild-type littermates and had significantly higher percentages of abdominal fat. The constituent adipocytes were found to have a mean cross-sectional area that was more than double that of corresponding cells from wild-type mice. However, food intake and locomotion were not significantly different between the two strains. These studies with humans, rats and mice implicate RGS9-2 as a factor in regulating body weight.


Assuntos
Peso Corporal/genética , Estudos de Associação Genética , Proteínas RGS/genética , Adipócitos/metabolismo , Adipócitos/patologia , Tecido Adiposo/patologia , Animais , Sequência de Bases , Índice de Massa Corporal , Feminino , Genes Reporter/genética , Humanos , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/patologia , Íntrons/genética , Masculino , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Atividade Motora , Núcleo Accumbens/metabolismo , Splicing de RNA/genética , Ratos , Deleção de Sequência/genética , Redução de Peso/genética
6.
Neurosci Lett ; 501(1): 31-4, 2011 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-21741448

RESUMO

The regulator of G protein signaling 9-2 (RGS9-2) is a constituent of G protein-coupled receptor (GPCR) macromolecular complexes with a major role in regulation of GPCR activity in the central nervous system. Previous in situ hybridization and Western blot studies revealed that RGS9-2 is expressed in the superficial dorsal horn of the spinal cord. In the present study, we monitored tail withdrawal latencies to noxious thermal stimuli and performed in vitro whole-cell patch clamp electrophysiological recordings from neurons in lamina II of the spinal dorsal horn to examine the role of RGS9-2 in the dorsal horn of the spinal cord in nociceptive behaviours and opiate mediated modulation of synaptic transmission. Our findings obtained from RGS9 knockout mice indicate that the lack of RGS9-2 protein decreases sensitivity to thermal stimuli and to the analgesic actions of morphine in the tail immersion paradigm. This modulatory role of RGS9-2 on opiate-mediated responses was further supported by electrophysiological studies showing that hyperpolarization of neurons in lamina II of the spinal dorsal horn evoked by application of DAMGO ([d-Ala2, N-MePhe4, Gly-ol]-enkephalin, a mu opioid receptor agonist) was diminished in RGS9 knockout mice. The results indicate that RGS9-2 enhances the effect of morphine and may play a crucial role in opiate-mediated analgesic mechanisms at the level of the spinal cord.


Assuntos
Comportamento Animal/fisiologia , Dor/metabolismo , Células do Corno Posterior/metabolismo , Proteínas RGS/metabolismo , Receptores Opioides mu/metabolismo , Transmissão Sináptica/fisiologia , Analgésicos Opioides/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Ala(2)-MePhe(4)-Gly(5)-Encefalina/farmacologia , Masculino , Camundongos , Camundongos Knockout , Morfina/farmacologia , Dor/fisiopatologia , Células do Corno Posterior/efeitos dos fármacos , Proteínas RGS/genética , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Medula Espinal/fisiopatologia , Transmissão Sináptica/efeitos dos fármacos
7.
J Neurosci ; 31(15): 5617-24, 2011 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-21490202

RESUMO

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 µ-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 Gα 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 Gα subunits, but morphine uniquely promotes an association between RGS9-2 and Gαi3. In contrast, RGS9-2/Gαq 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, Gß5, and Gαq. 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.


Assuntos
Analgésicos Opioides/farmacologia , Corpo Estriado/fisiologia , Proteínas RGS/fisiologia , Animais , Arrestinas/genética , Arrestinas/fisiologia , Western Blotting , Corpo Estriado/efeitos dos fármacos , Tolerância a Medicamentos , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/fisiologia , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Imunoprecipitação , Camundongos , Camundongos Knockout , Morfina/farmacologia , Fosfolipase C beta/metabolismo , Fosforilação , Proteínas RGS/efeitos dos fármacos , Proteínas RGS/genética , Receptores Opioides mu/agonistas , Receptores Opioides mu/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , beta-Arrestinas
8.
Trends Pharmacol Sci ; 30(3): 105-11, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19211160

RESUMO

Regulators of G-protein signaling (RGS proteins) comprise a large family of signal transduction molecules that modulate G-protein-coupled-receptor (GPCR) function. Among the RGS proteins expressed in the brain, RGS9-2 is very abundant in the striatum, a brain region involved in movement, motivation, mood and addiction. This protein negatively modulates signal transduction thus playing a key part in striatal function and resultant behavioral responses. In particular, there is evidence of important interactions with mu-opioid- and dopamine D(2)-receptor signaling pathways. Several studies indicate that manipulations of RGS9-2 levels in the striatum might greatly affect pharmacological responses. These findings indicate that treatment strategies targeting RGS9-2 levels or activity might be used to enhance responses to drugs acting at GPCRs and/or prevent undesired drug actions.


Assuntos
Proteínas RGS/fisiologia , Receptores Acoplados a Proteínas G/fisiologia , Animais , Antiparkinsonianos/efeitos adversos , Antipsicóticos/efeitos adversos , Estimulantes do Sistema Nervoso Central/efeitos adversos , Discinesia Induzida por Medicamentos/etiologia , Discinesia Induzida por Medicamentos/prevenção & controle , Humanos , Transtornos Relacionados ao Uso de Opioides/metabolismo , Transtornos Relacionados ao Uso de Opioides/psicologia , Proteínas RGS/biossíntese , Receptores de Dopamina D2/fisiologia , Receptores Opioides mu/fisiologia , Recompensa , Transdução de Sinais
9.
Prog Mol Biol Transl Sci ; 86: 299-333, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-20374720

RESUMO

Regulators of G protein signaling (RGS) comprise a diverse group of about 40 proteins which determine signaling amplitude and duration via modulation of receptor/G protein or receptor/effector coupling. Several members of the RGS family are expressed in the brain, where they have precise roles in regulation of important physiological processes. The unique functions of each RGS can be attributed to its structure, distinct pattern of expression, and regulation, and its preferential interactions with receptors, Galpha subunits and other signaling proteins. Evidence suggests dysfunction of RGS proteins is related to several neuropathological conditions. Moreover, clinical and preclinical work reveals that the efficacy and/or side effects of treatments are highly influenced by RGS activity. This article summarizes findings on RGS proteins in vulnerability to several neuropsychiatric disorders, the mechanism via which RGS proteins control neuronal responses and their potential use as drug targets.


Assuntos
Transtornos Mentais/metabolismo , Proteínas RGS/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Sobrevivência Celular , Humanos , Neurônios/metabolismo , Neurônios/patologia , Receptores Acoplados a Proteínas G/metabolismo
10.
Biotechnol J ; 3(12): 1555-63, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19072910

RESUMO

Over the last few years, a large number of preclinical and clinical studies have demonstrated the potential of gene therapy applications using adeno-associated viral (AAV) vectors. Gene transfer via AAV vectors has been particularly successful for the treatment or adjunct therapy of several CNS disorders. The present review summarizes the progress on AAV gene delivery models for three different CNS disorders. In particular, we discuss advances in AAV-mediated gene transfer strategies in animal models of Parkinson's disease, Alzheimer's disease and spinal cord trauma and summarize the results from the first clinical studies using AAV systems.


Assuntos
Adenoviridae/genética , Terapia Genética/tendências , Vetores Genéticos/genética , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/terapia , Traumatismos da Medula Espinal/genética , Traumatismos da Medula Espinal/terapia , Transfecção/tendências , Animais , Humanos
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