Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 13 de 13
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Neurochem Int ; 169: 105567, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37348761

RESUMO

COVID-19 affects primarily the lung. However, several other systemic alterations, including muscle weakness, fatigue and myalgia have been reported and may contribute to the disease outcome. We hypothesize that changes in the neuromuscular system may contribute to the latter symptoms observed in COVID-19 patients. Here, we showed that C57BL/6J mice inoculated intranasally with the murine betacoronavirus hepatitis coronavirus 3 (MHV-3), a model for studying COVID-19 in BSL-2 conditions that emulates severe COVID-19, developed robust motor alterations in muscle strength and locomotor activity. The latter changes were accompanied by degeneration and loss of motoneurons that were associated with the presence of virus-like particles inside the motoneuron. At the neuromuscular junction level, there were signs of atrophy and fragmentation in synaptic elements of MHV-3-infected mice. Furthermore, there was muscle atrophy and fiber type switch with alteration in myokines levels in muscles of MHV-3-infected mice. Collectively, our results show that acute infection with a betacoronavirus leads to robust motor impairment accompanied by neuromuscular system alteration.


Assuntos
COVID-19 , Vírus da Hepatite Murina , Camundongos , Animais , Camundongos Endogâmicos C57BL , Neurônios Motores , Junção Neuromuscular , Vírus da Hepatite Murina/fisiologia
2.
Exp Physiol ; 107(8): 933-945, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35478205

RESUMO

NEW FINDINGS: What is the central question of this study? We investigated the effects of intrathecal administration of a novel toxin, CTK 01512-2, in a mouse model of Huntington's disease. We asked whether spinal cord neurons can represent a therapeutic target, given that the spinal cord seems to be involved in motor symptoms of Huntington's disease. Pharmacological approaches focusing on the spinal cord and skeletal muscles might represent a more feasible strategy than a high-risk brain intervention. What is the main finding and its importance? We provided evidence of a novel, local, neuroprotective effect of CTK 01512-2, paving a path for the development of approaches to treat motor symptoms of Huntington's disease beyond the brain. ABSTRACT: Phα1ß is a neurotoxin from the venom of the Phoneutria nigriventer spider, available as CTK 01512-2, a recombinant peptide. Owing to its antinociceptive and analgesic properties, CTK 01512-2 has been described to alleviate neuroinflammatory responses. Despite the diverse actions of CTK 01512-2 on the nervous system, little is known regarding its neuroprotective effect, especially in neurodegenerative conditions such as Huntington's disease (HD), a genetic movement disorder without cure. Here, we investigated whether CTK 01512-2 has a neuroprotective effect in a mouse model of HD. We hypothesized that spinal cord neurons might represent a therapeutic target, because the spinal cord seems to be involved in the motor symptoms of HD (BACHD) mice. We treated BACHD mice with CTK 01512-2 by intrathecal injection and performed in vivo motor behavioural and morphological analyses in the CNS (brain and spinal cord) and muscles. Our data showed that intrathecal injection of CTK 01512-2 significantly improved motor performance in the open field task. CTK 01512-2 protected neurons in the spinal cord (but not in the brain) from death, suggesting a local effect. CTK 01512-2 exerted its neuroprotective effect by inhibiting BACHD neuronal apoptosis, as revealed by a reduction in caspase-3 in the spinal cord. CTK 01512-2 was also able to revert BACHD muscle atrophy. In conclusion, our data suggest a novel role for CTK 01512-2 acting directly in the spinal cord to ameliorate morphofunctional aspects of spinal cord neurons and muscles and improve the performance of BACHD mice in motor behavioural tests. Given that HD shares similar symptoms with many neurodegenerative conditions, the findings presented herein might also be applicable to other disorders.


Assuntos
Doença de Huntington , Fármacos Neuroprotetores , Animais , Modelos Animais de Doenças , Doença de Huntington/tratamento farmacológico , Doença de Huntington/genética , Camundongos , Camundongos Transgênicos , Neurônios , Fármacos Neuroprotetores/farmacologia , Medula Espinal
3.
Sleep ; 44(4)2021 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-33221910

RESUMO

STUDY OBJECTIVES: Cognitive behavioral therapy for insomnia (CBTI) for comorbid insomnia and obstructive sleep apnea (OSA) has had mixed results. We integrated CBTI with a positive airway pressure (PAP) adherence program and tested effects on sleep and PAP use. METHODS: 125 veterans (mean age 63.2, 96% men, 39% non-Hispanic white, 26% black/African American, 18% Hispanic/Latino) with comorbid insomnia and newly-diagnosed OSA (apnea-hypopnea index ≥ 15) were randomized to 5-weekly sessions integrating CBTI with a PAP adherence program provided by a "sleep coach" (with behavioral sleep medicine supervision), or 5-weekly sleep education control sessions. Participants and assessment staff were blinded to group assignment. Outcomes (baseline, 3 and 6 months) included Pittsburgh Sleep Quality Index (PSQI), 7-day sleep diary (sleep onset latency [SOL-D], wake after sleep onset [WASO-D], sleep efficiency [SE-D]), 7-day actigraphy (SE-A), and objective PAP use (hours/night and nights ≥ 4 h). Insomnia Severity Index (ISI), Epworth Sleepiness Scale (ESS), and Functional Outcomes of Sleep Questionnaire-10 (FOSQ-10) were also collected. RESULTS: Compared to controls, intervention participants showed greater improvement (baseline to 3 and 6 months, respectively) in PSQI (-3.2 and -1.7), SOL-D (-16.2 and -15.5 minutes), SE-D (10.5% and 8.5%), SE-A (4.4% and 2.6%) and more 90-day PAP use (1.3 and 0.9 more hours/night, 17.4 and 11.3 more nights PAP ≥ 4 h). 90-day PAP use at 3 months was 3.2 and 1.9 h/night in intervention versus controls. Intervention participants also had greater improvements in ISI, ESS, and FOSQ-10 (all p < 0.05). CONCLUSIONS: An intervention integrating CBTI with a PAP adherence program delivered by a supervised sleep coach improved sleep and PAP use in adults with comorbid insomnia and OSA. TRIAL REGISTRATION: ClinicalTrials.govStudy name: Novel Treatment of Comorbid Insomnia and Sleep Apnea in Older VeteransURL: https://clinicaltrials.gov/ct2/results?cond=&term=NCT02027558&cntry=&state=&city=&dist=Registration: NCT02027558.


Assuntos
Apneia Obstrutiva do Sono , Distúrbios do Início e da Manutenção do Sono , Veteranos , Adulto , Idoso , Pressão Positiva Contínua nas Vias Aéreas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polissonografia , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/epidemiologia , Apneia Obstrutiva do Sono/terapia , Distúrbios do Início e da Manutenção do Sono/complicações , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Distúrbios do Início e da Manutenção do Sono/terapia , Resultado do Tratamento
4.
Front Aging Neurosci ; 10: 274, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30271340

RESUMO

We examined whether baseline self-reported physical activity is associated with the efficacy of cognitive behavioral therapy for insomnia (CBT-I) in older veterans. Community-dwelling veterans aged 60 years and older with insomnia received CBT-I in a randomized controlled trial. Participants who received active treatment were divided into low and high physical activity based on self-report. Sleep outcomes were measured by sleep diary, questionnaire and wrist actigraphy; collected at baseline, post-treatment, 6-month and 12-month follow-up. Mixed-effects models compared differences between physical activity groups in change in sleep outcome from baseline to each follow-up, and equivalence tests examined if physical activity groups were clinically equal. There were no significant differences in sleep outcomes between physical activity groups. Equivalence tests suggested possible equality in physical activity groups for five of seven sleep outcomes. Efficacy of CBT-I in older veterans was not associated with self-reported physical activity at baseline. Older adults with insomnia who report low levels of physical activity can benefit from CBT-I.

5.
J Am Geriatr Soc ; 64(9): 1830-8, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27550552

RESUMO

OBJECTIVES: To test a new cognitive behavioral therapy for insomnia (CBT-I) program designed for use by nonclinicians. DESIGN: Randomized controlled trial. SETTING: Department of Veterans Affairs healthcare system. PARTICIPANTS: Community-dwelling veterans aged 60 and older who met diagnostic criteria for insomnia of 3 months duration or longer (N = 159). INTERVENTION: Nonclinician "sleep coaches" delivered a five-session manual-based CBT-I program including stimulus control, sleep restriction, sleep hygiene, and cognitive therapy (individually or in small groups), with weekly telephone behavioral sleep medicine supervision. Controls received five sessions of general sleep education. MEASUREMENTS: Primary outcomes, including self-reported (7-day sleep diary) sleep onset latency (SOL-D), wake after sleep onset (WASO-D), total wake time (TWT-D), and sleep efficiency (SE-D); Pittsburgh Sleep Quality Index (PSQI); and objective sleep efficiency (7-day wrist actigraphy, SE-A) were measured at baseline, at the posttreatment assessment, and at 6- and 12-month follow-up. Additional measures included the Insomnia Severity Index (ISI), depressive symptoms (Patient Health Questionnaire-9 (PHQ-9)), and quality of life (Medical Outcomes Study 12-item Short-form Survey version 2 (SF-12v2)). RESULTS: Intervention subjects had greater improvement than controls between the baseline and posttreatment assessments, the baseline and 6-month assessments, and the baseline and 12-month assessments in SOL-D (-23.4, -15.8, and -17.3 minutes, respectively), TWT-D (-68.4, -37.0, and -30.9 minutes, respectively), SE-D (10.5%, 6.7%, and 5.4%, respectively), PSQI (-3.4, -2.4, and -2.1 in total score, respectively), and ISI (-4.5, -3.9, and -2.8 in total score, respectively) (all P < .05). There were no significant differences in SE-A, PHQ-9, or SF-12v2. CONCLUSION: Manual-based CBT-I delivered by nonclinician sleep coaches improves sleep in older adults with chronic insomnia.


Assuntos
Terapia Cognitivo-Comportamental/métodos , Pessoal de Saúde , Distúrbios do Início e da Manutenção do Sono/psicologia , Distúrbios do Início e da Manutenção do Sono/terapia , Veteranos/psicologia , Idoso , Idoso de 80 Anos ou mais , Doença Crônica , Transtorno Depressivo/psicologia , Transtorno Depressivo/terapia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Psicometria/estatística & dados numéricos , Qualidade de Vida/psicologia , Reprodutibilidade dos Testes , Inquéritos e Questionários , Resultado do Tratamento , Vigília
6.
Cell Rep ; 2(4): 799-806, 2012 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-23022481

RESUMO

Mutations in the RNA binding protein FUS cause amyotrophic lateral sclerosis (ALS), a fatal adult motor neuron disease. Decreased expression of SMN causes the fatal childhood motor neuron disorder spinal muscular atrophy (SMA). The SMN complex localizes in both the cytoplasm and nuclear Gems, and loss of Gems is a cellular hallmark of fibroblasts in patients with SMA. Here, we report that FUS associates with the SMN complex, mediated by U1 snRNP and by direct interactions between FUS and SMN. Functionally, we show that FUS is required for Gem formation in HeLa cells, and expression of FUS containing a severe ALS-causing mutation (R495X) also results in Gem loss. Strikingly, a reduction in Gems is observed in ALS patient fibroblasts expressing either mutant FUS or TDP-43, another ALS-causing protein that interacts with FUS. The physical and functional interactions among SMN, FUS, TDP-43, and Gems indicate that ALS and SMA share a biochemical pathway, providing strong support for the view that these motor neuron diseases are related.


Assuntos
Esclerose Lateral Amiotrófica/metabolismo , Atrofia Muscular Espinal/metabolismo , Proteína FUS de Ligação a RNA/metabolismo , Proteínas do Complexo SMN/metabolismo , Esclerose Lateral Amiotrófica/patologia , Proteína DEAD-box 20/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Células HeLa , Humanos , Atrofia Muscular Espinal/patologia , Mutação , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Proteína FUS de Ligação a RNA/antagonistas & inibidores , Proteína FUS de Ligação a RNA/genética , Ribonucleoproteínas Nucleares Pequenas/metabolismo , Proteínas do Complexo SMN/genética
7.
PLoS One ; 7(10): e46663, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23056392

RESUMO

As synapses form and mature the synaptic partners produce organizing molecules that regulate each other's differentiation and ensure precise apposition of pre- and post-synaptic specializations. At the skeletal neuromuscular junction (NMJ), these molecules include agrin, a nerve-derived organizer of postsynaptic differentiation, and synaptic laminins, muscle-derived organizers of presynaptic differentiation. Both become concentrated in the synaptic cleft as the NMJ develops and are retained in adulthood. Here, we used mutant mice to ask whether these organizers are also required for synaptic maintenance. Deletion of agrin from a subset of adult motor neurons resulted in the loss of acetylcholine receptors and other components of the postsynaptic apparatus and synaptic cleft. Nerve terminals also atrophied and eventually withdrew from muscle fibers. On the other hand, mice lacking the presynaptic organizer laminin-α4 retained most of the synaptic cleft components but exhibited synaptic alterations reminiscent of those observed in aged animals. Although we detected no marked decrease in laminin or agrin levels at aged NMJs, we observed alterations in the distribution and organization of these synaptic cleft components suggesting that such changes could contribute to age-related synaptic disassembly. Together, these results demonstrate that pre- and post-synaptic organizers actively function to maintain the structure and function of adult NMJs.


Assuntos
Agrina/metabolismo , Laminina/metabolismo , Junção Neuromuscular/metabolismo , Agrina/genética , Animais , Imuno-Histoquímica , Laminina/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios Motores/metabolismo , Neurônios Motores/fisiologia , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sinapses/metabolismo , Sinapses/fisiologia
8.
Neuron ; 74(5): 816-29, 2012 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-22681687

RESUMO

VIDEO ABSTRACT: Using light and serial electron microscopy, we show profound refinements in motor axonal branching and synaptic connectivity before and after birth. Embryonic axons become maximally connected just before birth when they innervate ∼10-fold more muscle fibers than in maturity. In some developing muscles, axons innervate almost every muscle fiber. At birth, each neuromuscular junction is coinnervated by approximately ten highly intermingled axons (versus one in adults). Extensive die off of terminal branches occurs during the first several postnatal days, leading to much sparser arbors that still span the same territory. Despite the extensive pruning, total axoplasm per neuron increases as axons elongate, thicken, and add more synaptic release sites on their remaining targets. Motor axons therefore initially establish weak connections with nearly all available postsynaptic targets but, beginning at birth, massively redistribute synaptic resources, concentrating many more synaptic sites on many fewer muscle fibers. Analogous changes in connectivity may occur in the CNS.


Assuntos
Axônios/fisiologia , Neurônios Motores/fisiologia , Desenvolvimento Muscular/fisiologia , Junção Neuromuscular/crescimento & desenvolvimento , Fatores Etários , Animais , Animais Recém-Nascidos , Axônios/ultraestrutura , Bungarotoxinas/metabolismo , Toxina da Cólera/metabolismo , Embrião de Mamíferos , Imageamento Tridimensional , Técnicas In Vitro , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Camundongos , Camundongos Transgênicos , Microscopia Confocal , Microscopia Eletrônica , Modelos Biológicos , Neurônios Motores/ultraestrutura , Junção Neuromuscular/embriologia , Junção Neuromuscular/ultraestrutura
9.
PLoS One ; 7(4): e34640, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22485182

RESUMO

Normal aging and neurodegenerative diseases both lead to structural and functional alterations in synapses. Comparison of synapses that are generally similar but respond differently to insults could provide the basis for discovering mechanisms that underlie susceptibility or resistance to damage. Here, we analyzed skeletal neuromuscular junctions (NMJs) in 16 mouse muscles to seek such differences. We find that muscles respond in one of three ways to aging. In some, including most limb and trunk muscles, age-related alterations to NMJs are progressive and extensive during the second postnatal year. NMJs in other muscles, such as extraocular muscles, are strikingly resistant to change. A third set of muscles, including several muscles of facial expression and the external anal sphinter, succumb to aging but not until the third postnatal year. We asked whether susceptible and resistant muscles differed in rostrocaudal or proximodistal position, source of innervation, motor unit size, or fiber type composition. Of these factors, muscle innervation by brainstem motor neurons correlated best with resistance to age-related decline. Finally, we compared synaptic alterations in normally aging muscles to those in a mouse model of amyotrophic lateral sclerosis (ALS). Patterns of resistance and susceptibility were strikingly correlated in the two conditions. Moreover, damage to NMJs in aged muscles correlated with altered expression and distribution of CRMP4a and TDP-43, which are both altered in motor neurons affected by ALS. Together, these results reveal novel structural, regional and molecular parallels between aging and ALS.


Assuntos
Envelhecimento , Esclerose Lateral Amiotrófica/metabolismo , Músculo Esquelético/inervação , Junção Neuromuscular/metabolismo , Esclerose Lateral Amiotrófica/patologia , Animais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Expressão Gênica , Regulação da Expressão Gênica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios Motores/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/patologia , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Junção Neuromuscular/patologia , Receptores Colinérgicos/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase-1
10.
Proc Natl Acad Sci U S A ; 107(33): 14863-8, 2010 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-20679195

RESUMO

The cellular basis of age-related behavioral decline remains obscure but alterations in synapses are likely candidates. Accordingly, the beneficial effects on neural function of caloric restriction and exercise, which are among the most effective anti-aging treatments known, might also be mediated by synapses. As a starting point in testing these ideas, we studied the skeletal neuromuscular junction (NMJ), a large, accessible peripheral synapse. Comparison of NMJs in young adult and aged mice revealed a variety of age-related structural alterations, including axonal swellings, sprouting, synaptic detachment, partial or complete withdrawal of axons from some postsynaptic sites, and fragmentation of the postsynaptic specialization. Alterations were significant by 18 mo of age and severe by 24 mo. A life-long calorie-restricted diet significantly decreased the incidence of pre- and postsynaptic abnormalities in 24-mo-old mice and attenuated age-related loss of motor neurons and turnover of muscle fibers. One month of exercise (wheel running) in 22-mo-old mice also reduced age-related synaptic changes but had no effect on motor neuron number or muscle fiber turnover. Time-lapse imaging in vivo revealed that exercise partially reversed synaptic alterations that had already occurred. These results demonstrate a critical effect of aging on synaptic structure and provide evidence that interventions capable of extending health span and lifespan can partially reverse these age-related synaptic changes.


Assuntos
Envelhecimento/fisiologia , Restrição Calórica , Junção Neuromuscular/fisiopatologia , Condicionamento Físico Animal/fisiologia , Animais , Imuno-Histoquímica , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Confocal , Neurônios Motores/metabolismo , Neurônios Motores/fisiologia , Músculo Esquelético/anormalidades , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Junção Neuromuscular/anormalidades , Junção Neuromuscular/metabolismo , Receptores Colinérgicos/metabolismo , Sinapses/metabolismo
11.
Proc Natl Acad Sci U S A ; 106(49): 20960-5, 2009 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-19933335

RESUMO

During injury to the nervous system, innate immune cells mediate phagocytosis of debris, cytokine production, and axon regeneration. In the neuro-degenerative disease amyotrophic lateral sclerosis (ALS), innate immune cells in the CNS are activated. However, the role of innate immunity in the peripheral nervous system (PNS) has not been well defined. In this study, we characterized robust activation of CD169/CD68/Iba1+ macrophages throughout the PNS in mutant SOD1(G93A) and SOD1(G37R) transgenic mouse models of ALS. Macrophage activation occurred pre-symptomatically, and expanded from focal arrays within nerve bundles to a tissue-wide distribution following symptom onset. We found a striking dichotomy for immune cells within the spinal cord and PNS. Flow cytometry and GFP bone marrow chimeras showed that spinal cord microglia were mainly tissue resident derived, dendritic-like cells, whereas in peripheral nerves, the majority of activated macrophages infiltrated from the circulation. Humoral antibodies and complement localized to PNS tissue in tandem with macrophage recruitment, and deficiency in complement C4 led to decreased macrophage activation. Therefore, cross-talk between nervous and immune systems occurs throughout the PNS during ALS disease progression. These data reveal a progressive innate and humoral immune response in peripheral nerves that is separate and distinct from spinal cord immune activation in ALS transgenic mice.


Assuntos
Esclerose Lateral Amiotrófica/imunologia , Imunidade Humoral/imunologia , Imunidade Inata/imunologia , Sistema Nervoso Periférico/imunologia , Sistema Nervoso Periférico/patologia , Envelhecimento/imunologia , Envelhecimento/patologia , Esclerose Lateral Amiotrófica/enzimologia , Esclerose Lateral Amiotrófica/patologia , Animais , Complemento C4/imunologia , Citometria de Fluxo , Proteínas de Fluorescência Verde/metabolismo , Ativação de Macrófagos/imunologia , Camundongos , Camundongos Transgênicos , Músculos/inervação , Músculos/patologia , Mutação/genética , Células Mieloides/imunologia , Células Mieloides/patologia , Degeneração Neural/imunologia , Degeneração Neural/patologia , Sistema Nervoso Periférico/enzimologia , Fenótipo , Nervo Isquiático/patologia , Medula Espinal/imunologia , Medula Espinal/patologia , Coloração e Rotulagem , Superóxido Dismutase/genética
12.
Brain Res Brain Res Rev ; 47(1-3): 33-45, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15572161

RESUMO

Glycine receptors (GlyRs) play a major role in the excitability of spinal cord and brain stem neurons. During development, several properties of these receptors undergo significant changes resulting in major modifications of their physiological functions. For example, the receptor structure switches from a monomeric alpha or heteromeric alpha 2 beta in immature neurons to an alpha 1 beta receptor type in mature neurons. Together with these changes in receptor subunits, the postsynaptic cluster size increases with development. Parallel to these modifications, the apparent receptor affinity to glycine and strychnine, as well as that of Zn(2+) and ethanol increases with time. The mature receptor is characterized by a slow desensitizing current and high sensitivity to modulation by protein kinase C. Also, the high level of glycinergic transmission in immature spinal neurons modulates neuronal excitability causing membrane depolarization and changes in intracellular calcium. Due to these properties, chronic inhibition of glycinergic transmission affects neurite outgrowth and produces changes in the level of synaptic transmission induced by GABA(A) and AMPA receptors. Finally, the high level of plasticity found in immature GlyRs is likely associated to changes in cytoskeleton dynamics.


Assuntos
Encéfalo/metabolismo , Diferenciação Celular/fisiologia , Inibição Neural/fisiologia , Terminações Pré-Sinápticas/metabolismo , Receptores de Glicina/metabolismo , Animais , Encéfalo/crescimento & desenvolvimento , Glicinérgicos/farmacologia , Humanos , Plasticidade Neuronal/fisiologia , Subunidades Proteicas/metabolismo , Agregação de Receptores/fisiologia , Receptores de Glicina/efeitos dos fármacos , Transmissão Sináptica/fisiologia
13.
Nat Neurosci ; 6(8): 819-24, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12858180

RESUMO

Glycine receptors (GlyRs), together with GABA(A) and nicotinic acetylcholine (ACh) receptors, form part of the ligand-activated ion channel superfamily and regulate the excitability of the mammalian brain stem and spinal cord. Here we report that the ability of the neurotransmitter glycine to gate recombinant and native ionotropic GlyRs is modulated by the G protein betagamma dimer (Gbetagamma). We found that the amplitude of the glycine-activated Cl- current was enhanced after application of purified Gbetagamma or after activation of a G protein-coupled receptor. Overexpression of three distinct G protein alpha subunits (Galpha), as well as the Gbetagamma scavenger peptide ct-GRK2, significantly blunted the effect of G protein activation. Single-channel recordings from isolated membrane patches showed that Gbetagamma increased the GlyR open probability (nP(o)). Our results indicate that this interaction of Gbetagamma with GlyRs regulates both motor and sensory functions in the central nervous system.


Assuntos
Glicina/farmacologia , Proteínas Heterotriméricas de Ligação ao GTP/farmacologia , Canais Iônicos/efeitos dos fármacos , Canais Iônicos/metabolismo , Animais , Células Cultivadas , Canais de Cloreto/fisiologia , Condutividade Elétrica , Eletrofisiologia , Proteínas de Ligação ao GTP/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Peptídeos/farmacologia , Receptores de Glicina/efeitos dos fármacos , Receptores de Glicina/metabolismo , Receptores de Glicina/fisiologia , Medula Espinal/citologia , Medula Espinal/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...