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[PMID]:28457669
[Au] Autor:Kamens HM; Peck C; Garrity C; Gechlik A; Jenkins BC; Rajan A
[Ad] Endereço:Department of Biobehavioral Health, Penn State University, University Park, PA, USA; Center for Brain, Behavior, and Cognition, Penn State University, University Park, PA, USA. Electronic address: hmk123@psu.edu.
[Ti] Título:α6ß2 nicotinic acetylcholine receptors influence locomotor activity and ethanol consumption.
[So] Source:Alcohol;61:43-49, 2017 Jun.
[Is] ISSN:1873-6823
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Nicotinic acetylcholine receptors (nAChRs) in the mesolimbic dopamine system have been implicated in ethanol behaviors. In particular, work in genetically engineered mice has demonstrated that α6-containing nAChRs are involved in ethanol consumption and sedation. A limitation of these studies is that the alteration in the receptor was present throughout development. The recently described α6ß2 antagonist, N,N-decane-1,10-diyl-bis-3-picolinium diiodide (bPiDI), now makes it possible to test for the involvement of these receptors using a pharmacological approach. The aim of this study was to examine the role of α6ß2 nAChRs in ethanol behaviors using a pharmacological approach. Adolescent C57BL/6J mice were treated with bPiDI 30 min prior to testing the mice for binge-like ethanol consumption in the drinking-in-the-dark (DID) test, ethanol-induced motor incoordination using the balance beam, and ethanol-induced sedation using the Loss of Righting Reflex (LORR) paradigm. Adolescent animals were chosen because they express a high amount of α6 mRNA relative to adult animals. Control studies were also performed to determine the effect of bPiDI on locomotor activity and ethanol metabolism. Female mice treated with 20 mg/kg bPiDI had reduced locomotor activity compared to saline-treated animals during the first 30 min following an acute injection. Pretreatment with the α6ß2 antagonist reduced adolescent ethanol consumption but also reduced saccharin consumption. No significant effects were observed on ethanol-induced ataxia, sedation, or metabolism. This study provides evidence that α6ß2 nAChRs are involved in locomotor activity as well as ethanol and saccharin consumption in adolescent animals.
[Mh] Termos MeSH primário: Consumo de Bebidas Alcoólicas/fisiopatologia
Etanol/administração & dosagem
Locomoção/efeitos dos fármacos
Receptores Nicotínicos/fisiologia
[Mh] Termos MeSH secundário: Consumo de Bebidas Alcoólicas/prevenção & controle
Animais
Bebedeira/fisiopatologia
Etanol/efeitos adversos
Feminino
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Antagonistas Nicotínicos/farmacologia
Picolinas/farmacologia
Compostos de Piridínio/farmacologia
Sacarina/administração & dosagem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (N,N-decane-1,10-diyl-bis-3-picolinium); 0 (Nicotinic Antagonists); 0 (Picolines); 0 (Pyridinium Compounds); 0 (Receptors, Nicotinic); 0 (alpha6beta2 nicotinic acetylcholine receptor); 3K9958V90M (Ethanol); FST467XS7D (Saccharin)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE


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[PMID]:29240768
[Au] Autor:Jeong JE; Rhee JK; Kim TM; Kwak SM; Bang SH; Cho H; Cheon YH; Min JA; Yoo GS; Kim K; Choi JS; Choi SW; Kim DJ
[Ad] Endereço:Department of Psychiatry, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
[Ti] Título:The association between the nicotinic acetylcholine receptor α4 subunit gene (CHRNA4) rs1044396 and Internet gaming disorder in Korean male adults.
[So] Source:PLoS One;12(12):e0188358, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The primary aim of this study was to investigate the genetic predisposition of Internet gaming disorder (IGD), and the secondary aim was to compare the results to those of alcohol dependence (AD). Two independent case-control studies were conducted. A total of 30 male participants with IGD, diagnosed according to the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria, and 30 sex-matched controls participated in study 1. We designed targeted exome sequencing (TES) to test for 72 candidate genes that have been implicated in the pathogenesis of addiction. The genes included seven neurotransmitter (dopamine, serotonin, glutamate, r-aminobutyric acid (GABA), norepinephrine, acetylcholine, and opioid) system genes. A total of 31 male in-patients with AD and 29 normal male controls (NC) were enrolled in study 2. The same 72 genes included in study 1 and ten additional genes related to alcohol-metabolic enzyme were selected as the target genes, and we identified the genetic variants using the same method (TES). The IGD group had a lower frequency of the T allele of rs1044396 in the nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4), and this variant represents a protective allele against IGD. However, we did not find a significant difference in the polymorphisms of the 72 genes that encode neurotransmitter systems between the AD and NC groups. This study demonstrated that rs1044396 of CHRNA4 was significantly associated with IGD.
[Mh] Termos MeSH primário: Comportamento Aditivo/genética
Internet
Receptores Nicotínicos/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Estudos de Casos e Controles
Seres Humanos
Masculino
Polimorfismo de Nucleotídeo Único
República da Coreia
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Nicotinic); 0 (nicotinic acetylcholine receptor alpha4 subunit)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180223
[Lr] Data última revisão:
180223
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171215
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0188358


  3 / 13581 MEDLINE  
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[PMID]:29293602
[Au] Autor:Qian J; Mummalaneni S; Grider JR; Damaj MI; Lyall V
[Ad] Endereço:Physiology and Biophysics Virginia Commonwealth University, Richmond, VA, United States of America.
[Ti] Título:Nicotinic acetylcholine receptors (nAChRs) are expressed in Trpm5 positive taste receptor cells (TRCs).
[So] Source:PLoS One;13(1):e0190465, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Nicotine evokes chorda tympani (CT) taste nerve responses and an aversive behavior in Trpm5 knockout (KO) mice. The agonists and antagonists of nicotinic acetylcholine receptors (nAChRs) modulate neural and behavioral responses to nicotine in wildtype (WT) mice, Trpm5 KO mice and rats. This indicates that nicotine evokes bitter taste by activating a Trpm5-dependent pathway and a Trpm5-independent but nAChR-dependent pathway. Rat CT responses to ethanol are also partially inhibited by nAChR blockers, mecamylamine and dihydro-ß-erythroidine. This indicates that a component of the bitter taste of ethanol is also nAChR-dependent. However, at present the expression and localization of nAChR subunits has not been investigated in detail in taste receptor cells (TRCs). To this end, in situ hybridization, immunohistochemistry and q-RT-PCR techniques were utilized to localize nAChR subunits in fungiform and circumvallate TRCs in WT mice, Trpm5-GFP transgenic mice, nAChR KO mice, and rats. The expression of mRNAs for α7, ß2 and ß4 nAChR subunits was observed in a subset of rat and WT mouse circumvallate and fungiform TRCs. Specific α3, α4, α7, ß2, and ß4 antibodies localized to a subset of WT mouse circumvallate and fungiform TRCs. In Trpm5-GFP mice α3, α4, α7, and ß4 antibody binding was observed in a subset of Trpm5-positive circumvallate TRCs. Giving nicotine (100 µg/ml) in drinking water to WT mice for 3 weeks differentially increased the expression of α3, α4, α5, α6, α7, ß2 and ß4 mRNAs in circumvallate TRCs to varying degrees. Giving ethanol (5%) in drinking water to WT mice induced an increase in the expression of α5 and ß4 mRNAs in circumvallate TRCs with a significant decrease in the expression of α3, α6 and ß2 mRNAs. We conclude that nAChR subunits are expressed in Trpm5-positive TRCs and their expression levels are differentially altered by chronic oral exposure to nicotine and ethanol.
[Mh] Termos MeSH primário: Receptores Nicotínicos/metabolismo
Canais de Cátion TRPM/metabolismo
Papilas Gustativas/fisiologia
[Mh] Termos MeSH secundário: Animais
Hibridização In Situ
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Ratos
Ratos Sprague-Dawley
Reação em Cadeia da Polimerase em Tempo Real
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Receptors, Nicotinic); 0 (TRPM Cation Channels); 0 (TRPM5 protein, rat); 0 (Trpm5 protein, mouse)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180221
[Lr] Data última revisão:
180221
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180103
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190465


  4 / 13581 MEDLINE  
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[PMID]:29283235
[Au] Autor:Silkis IG; Makechiv VA
[Ti] Título:Possible Mechanisms of Influence of Various Concentrations of Acetylcholine on Hippocampal Functioning.
[So] Source:Usp Fiziol Nauk;47(4):57-75, 2016 Oct-Dec.
[Is] ISSN:0301-1798
[Cp] País de publicação:Russia (Federation)
[La] Idioma:rus
[Ab] Resumo:Analysis of features of influence of acetylcholine on the hippocampal functioning was performed basing on the modulation rules for the efficacy of excitatory and inhibitory synaptic transmission we earlier proposed, and also on the known data about location of pre- and postsynaptic muscarine and nicotinic receptors. According to these rules, activation of postsynaptic muscarine М1/М3 and nicotinic receptors should promote long-term potentiation of excitatory and depressions (LTD) of inhibitory input to a neuron, whereas action on М2/М4 receptors should promote LTD of excitatory input and a decrease in neuromodulator release. If inhibitory input is stronger than excitatory, LTP (LTD) of excitatory input to the interneuron should promote LTD (LTP) of excitatory input to a target cell. It follows from the proposed mechanism that a lowing concentration of acetylcholine in the hippocampus, a decrease in density of М1/ М3 and a4p2 receptors, and augmenting binding of М2 receptors must lead to a depression of responses of pyramidal neurons in СА3 and СА1 fields to signals from the entorhinal cortex. Thereof, interaction of the semantic information, stored in the cortex, with the information of an episode-, stored in the hippocampus must be hindered and this effect can underlie disturbances of recall of stored information at Alzheimer's disease.
[Mh] Termos MeSH primário: Acetilcolina/farmacologia
Doença de Alzheimer/metabolismo
Agonistas Colinérgicos/farmacologia
Hipocampo/efeitos dos fármacos
Potenciação de Longa Duração/efeitos dos fármacos
Depressão Sináptica de Longo Prazo/efeitos dos fármacos
[Mh] Termos MeSH secundário: Acetilcolina/metabolismo
Doença de Alzheimer/genética
Doença de Alzheimer/fisiopatologia
Animais
Agonistas Colinérgicos/metabolismo
Córtex Entorrinal/efeitos dos fármacos
Córtex Entorrinal/fisiologia
Regulação da Expressão Gênica
Hipocampo/fisiologia
Seres Humanos
Potenciação de Longa Duração/fisiologia
Depressão Sináptica de Longo Prazo/fisiologia
Neurônios/citologia
Neurônios/efeitos dos fármacos
Neurônios/metabolismo
Receptores Muscarínicos/genética
Receptores Muscarínicos/metabolismo
Receptores Nicotínicos/genética
Receptores Nicotínicos/metabolismo
Sinapses/efeitos dos fármacos
Sinapses/fisiologia
Transmissão Sináptica/efeitos dos fármacos
Transmissão Sináptica/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Cholinergic Agonists); 0 (Receptors, Muscarinic); 0 (Receptors, Nicotinic); N9YNS0M02X (Acetylcholine)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180116
[Lr] Data última revisão:
180116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171229
[St] Status:MEDLINE


  5 / 13581 MEDLINE  
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[PMID]:28743602
[Au] Autor:Fait BW; Thompson DC; Mose TN; Jatlow P; Jordt SE; Picciotto MR; Mineur YS
[Ad] Endereço:Department of Psychiatry, Yale University School of Medicine, 34 Park Street, 3rd Floor Research, New Haven, CT 06520, USA.
[Ti] Título:Menthol disrupts nicotine's psychostimulant properties in an age and sex-dependent manner in C57BL/6J mice.
[So] Source:Behav Brain Res;334:72-77, 2017 09 15.
[Is] ISSN:1872-7549
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Menthol is a commonly used flavorant in tobacco and e-cigarettes, and could contribute to nicotine sensitivity. To understand how menthol could contribute to nicotine intake and addiction, it is important to determine whether specific mechanisms related to sex and age could underlie behavioral changes induced by menthol-laced nicotinic products. Using a validated paradigm of nicotine-dependent locomotor stimulation, adolescent and adult C57BL/6J mice of both sexes were exposed to nicotine, or nicotine laced with menthol, as their sole source of fluid, and psychostimulant effects were evaluated by recording home cage locomotor activity for ten days. Nicotine and cotinine blood levels were measured following exposure. Results show an interaction between treatment, age, and sex on liquid consumption, indicating that mice responded differently to menthol and nicotine based on their age and sex. Adult male mice greatly increased their nicotine intake when given menthol. In female mice of both age groups, menthol did not have this effect. Despite an increase in nicotine intake promoted by menthol, adult male mice showed a significant decrease in locomotion, suggesting that menthol blunted nicotine-induced psychostimulation. This behavioral response to menthol was not detected in adolescent mice of either sex. These data confirm that menthol is more than a flavorant, and can influence both nicotine intake and its psychostimulant effects. These results suggest that age- and sex-dependent mechanisms could underlie menthol's influence on nicotine intake and that studies including adolescent and adult menthol smokers of both sexes are warranted.
[Mh] Termos MeSH primário: Envelhecimento/efeitos dos fármacos
Estimulantes do Sistema Nervoso Central/farmacologia
Mentol/farmacologia
Nicotina/farmacologia
Psicotrópicos/farmacologia
Caracteres Sexuais
[Mh] Termos MeSH secundário: Envelhecimento/fisiologia
Animais
Estimulantes do Sistema Nervoso Central/sangue
Cotinina/sangue
Feminino
Masculino
Camundongos Endogâmicos C57BL
Atividade Motora/efeitos dos fármacos
Atividade Motora/fisiologia
Nicotina/sangue
Distribuição Aleatória
Receptores Nicotínicos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, U.S. GOV'T, P.H.S.
[Nm] Nome de substância:
0 (Central Nervous System Stimulants); 0 (Psychotropic Drugs); 0 (Receptors, Nicotinic); 0 (nicotinic receptor beta2); 1490-04-6 (Menthol); 6M3C89ZY6R (Nicotine); K5161X06LL (Cotinine)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180104
[Lr] Data última revisão:
180104
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170727
[St] Status:MEDLINE


  6 / 13581 MEDLINE  
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[PMID]:29206881
[Au] Autor:Parker RL; O'Neill HC; Henley BM; Wageman CR; Drenan RM; Marks MJ; Miwa JM; Grady SR; Lester HA
[Ad] Endereço:Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, United States of America.
[Ti] Título:Deletion of lynx1 reduces the function of α6* nicotinic receptors.
[So] Source:PLoS One;12(12):e0188715, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The α6 nicotinic acetylcholine receptor (nAChR) subunit is an attractive drug target for treating nicotine addiction because it is present at limited sites in the brain including the reward pathway. Lynx1 modulates several nAChR subtypes; lynx1-nAChR interaction sites could possibly provide drug targets. We found that dopaminergic cells from the substantia nigra pars compacta (SNc) express lynx1 mRNA transcripts and, as assessed by co-immunoprecipitation, α6 receptors form stable complexes with lynx1 protein, although co-transfection with lynx1 did not affect nicotine-induced currents from cell lines transfected with α6 and ß2. To test whether lynx1 is important for the function of α6 nAChRs in vivo, we bred transgenic mice carrying a hypersensitive mutation in the α6 nAChR subunit (α6L9'S) with lynx1 knockout mice, providing a selective probe of the effects of lynx1 on α6* nAChRs. Lynx1 removal reduced the α6 component of nicotine-mediated rubidium efflux and dopamine (DA) release from synaptosomal preparations with no effect on numbers of α6ß2 binding sites, indicating that lynx1 is functionally important for α6* nAChR activity. No effects of lynx1 removal were detected on nicotine-induced currents in slices from SNc, suggesting that lynx1 affects presynaptic α6* nAChR function more than somatic function. In the absence of agonist, lynx1 removal did not alter DA release in dorsal striatum as measured by fast scan cyclic voltammetry. Lynx1 removal affected some behaviors, including a novel-environment assay and nicotine-stimulated locomotion. Trends in 24-hour home-cage behavior were also suggestive of an effect of lynx1 removal. Conditioned place preference for nicotine was not affected by lynx1 removal. The results show that some functional and behavioral aspects of α6-nAChRs are modulated by lynx1.
[Mh] Termos MeSH primário: Proteínas Ligadas por GPI/genética
Receptores Nicotínicos/fisiologia
[Mh] Termos MeSH secundário: Animais
Dopamina/metabolismo
Células HEK293
Seres Humanos
Camundongos
Camundongos Transgênicos
Neurônios/metabolismo
RNA Mensageiro/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (GPI-Linked Proteins); 0 (LYNX1 protein, human); 0 (RNA, Messenger); 0 (Receptors, Nicotinic); 0 (nicotinic receptor alpha6); VTD58H1Z2X (Dopamine)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171229
[Lr] Data última revisão:
171229
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171206
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0188715


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[PMID]:28450546
[Au] Autor:Sun Y; Yang Y; Galvin VC; Yang S; Arnsten AF; Wang M
[Ad] Endereço:Department of Neurology, Peking University First Hospital, Beijing 100034.
[Ti] Título:Nicotinic α4ß2 Cholinergic Receptor Influences on Dorsolateral Prefrontal Cortical Neuronal Firing during a Working Memory Task.
[So] Source:J Neurosci;37(21):5366-5377, 2017 May 24.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The primate dorsolateral prefrontal cortex (dlPFC) subserves top-down regulation of attention and working memory abilities. Depletion studies show that the neuromodulator acetylcholine (ACh) is essential to dlPFC working memory functions, but the receptor and cellular bases for cholinergic actions are just beginning to be understood. The current study found that nicotinic receptors comprised of α4 and ß2 subunits (α4ß2-nAChR) enhance the task-related firing of delay and fixation cells in the dlPFC of monkeys performing a working memory task. Iontophoresis of α4ß2-nAChR agonists increased the neuronal firing and enhanced the spatial tuning of delay cells, neurons that represent visual space in the absence of sensory stimulation. These enhancing effects were reversed by coapplication of a α4ß2-nAChR antagonist, consistent with actions at α4ß2-nAChR. Delay cell firing was reduced when distractors were presented during the delay epoch, whereas stimulation of α4ß2-nAChR protected delay cells from these deleterious effects. Iontophoresis of α4ß2-nAChR agonists also enhanced the firing of fixation cells, neurons that increase firing when the monkey initiates a trial, and maintain firing until the trial is completed. These neurons are thought to contribute to sustained attention and top-down motor control and have never before been the subject of pharmacological inquiry. These findings begin to build a picture of the cellular actions underlying the beneficial effects of ACh on attention and working memory. The data may also help to explain why genetic insults to α4 subunits are associated with working memory and attentional deficits and why α4ß2-nAChR agonists may have therapeutic potential. The acetylcholine (ACh) arousal system in the brain is needed for robust attention and working memory functions, but the receptor and cellular bases for its beneficial effects are poorly understood in the newly evolved primate brain. The current study found that ACh stimulation of nicotinic receptors comprised of α4 and ß2 subunits (α4ß2-nAChR) enhanced the firing of neurons in the primate prefrontal cortex that subserve top-down attentional control and working memory. α4ß2-nAChR stimulation also protected neuronal responding from the detrimental effects of distracters presented during the delay epoch, when information is held in working memory. These results illuminate how ACh strengthens higher cognition and help to explain why genetic insults to the α4 subunit weaken cognitive and attentional abilities.
[Mh] Termos MeSH primário: Potenciais Evocados
Memória de Curto Prazo
Neurônios/metabolismo
Córtex Pré-Frontal/metabolismo
Receptores Nicotínicos/metabolismo
[Mh] Termos MeSH secundário: Animais
Macaca mulatta
Masculino
Neurônios/efeitos dos fármacos
Neurônios/fisiologia
Agonistas Nicotínicos/farmacologia
Córtex Pré-Frontal/citologia
Córtex Pré-Frontal/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nicotinic Agonists); 0 (Receptors, Nicotinic); 0 (nicotinic receptor alpha4beta2)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171124
[Lr] Data última revisão:
171124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.0364-17.2017


  8 / 13581 MEDLINE  
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[PMID]:29040265
[Au] Autor:Makino T; Nakamura R; Terakawa M; Muneoka S; Nagahira K; Nagane Y; Yamate J; Motomura M; Utsugisawa K
[Ad] Endereço:Drug Discovery Technology Function, Asubio Pharma Co., LTD, Kobe, Japan.
[Ti] Título:Analysis of peripheral B cells and autoantibodies against the anti-nicotinic acetylcholine receptor derived from patients with myasthenia gravis using single-cell manipulation tools.
[So] Source:PLoS One;12(10):e0185976, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The majority of patients with myasthenia gravis (MG), an organ-specific autoimmune disease, harbor autoantibodies that attack the nicotinic acetylcholine receptor (nAChR-Abs) at the neuromuscular junction of skeletal muscles, resulting in muscle weakness. Single cell manipulation technologies coupled with genetic engineering are very powerful tools to examine T cell and B cell repertoires and the dynamics of adaptive immunity. These tools have been utilized to develop mAbs in parallel with hybridomas, phage display technologies and B-cell immortalization. By applying a single cell technology and novel high-throughput cell-based binding assays, we identified peripheral B cells that produce pathogenic nAChR-Abs in patients with MG. Although anti-nAChR antibodies produced by individual peripheral B cells generally exhibited low binding affinity for the α-subunit of the nAChR and great sequence diversity, a small fraction of these antibodies bound with high affinity to native-structured nAChRs on cell surfaces. B12L, one such Ab isolated here, competed with a rat Ab (mAb35) for binding to the human nAChR and thus considered to recognize the main immunogenic region (MIR). By evaluating the Ab in in vitro cell-based assays and an in vivo rat passive transfer model, B12L was found to act as a pathogenic Ab in rodents and presumably in humans.These findings suggest that B cells in peripheral blood may impact MG pathogenicity. Our methodology can be applied not only to validate pathogenic Abs as molecular target of MG treatment, but also to discover and analyze Ab production systems in other human diseases.
[Mh] Termos MeSH primário: Linfócitos B/imunologia
Miastenia Gravis/imunologia
Subunidades Proteicas/imunologia
Receptores Nicotínicos/imunologia
Análise de Célula Única/métodos
[Mh] Termos MeSH secundário: Transferência Adotiva
Animais
Anticorpos Monoclonais/biossíntese
Anticorpos Monoclonais/química
Anticorpos Monoclonais/isolamento & purificação
Autoanticorpos/análise
Autoanticorpos/biossíntese
Linfócitos B/patologia
Citometria de Fluxo
Seres Humanos
Hibridomas/química
Hibridomas/imunologia
Miastenia Gravis/genética
Miastenia Gravis/patologia
Cultura Primária de Células
Subunidades Proteicas/antagonistas & inibidores
Subunidades Proteicas/genética
Ratos
Receptores Nicotínicos/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Autoantibodies); 0 (Protein Subunits); 0 (Receptors, Nicotinic)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171018
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0185976


  9 / 13581 MEDLINE  
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[PMID]:29023569
[Au] Autor:Vulfius CA; Kasheverov IE; Kryukova EV; Spirova EN; Shelukhina IV; Starkov VG; Andreeva TV; Faure G; Zouridakis M; Tsetlin VI; Utkin YN
[Ad] Endereço:Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, Russia.
[Ti] Título:Pancreatic and snake venom presynaptically active phospholipases A2 inhibit nicotinic acetylcholine receptors.
[So] Source:PLoS One;12(10):e0186206, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Phospholipases A2 (PLA2s) are enzymes found throughout the animal kingdom. They hydrolyze phospholipids in the sn-2 position producing lysophospholipids and unsaturated fatty acids, agents that can damage membranes. PLA2s from snake venoms have numerous toxic effects, not all of which can be explained by phospholipid hydrolysis, and each enzyme has a specific effect. We have earlier demonstrated the capability of several snake venom PLA2s with different enzymatic, cytotoxic, anticoagulant and antiproliferative properties, to decrease acetylcholine-induced currents in Lymnaea stagnalis neurons, and to compete with α-bungarotoxin for binding to nicotinic acetylcholine receptors (nAChRs) and acetylcholine binding protein. Since nAChRs are implicated in postsynaptic and presynaptic activities, in this work we probe those PLA2s known to have strong presynaptic effects, namely ß-bungarotoxin from Bungarus multicinctus and crotoxin from Crotalus durissus terrificus. We also wished to explore whether mammalian PLA2s interact with nAChRs, and have examined non-toxic PLA2 from porcine pancreas. It was found that porcine pancreatic PLA2 and presynaptic ß-bungarotoxin blocked currents mediated by nAChRs in Lymnaea neurons with IC50s of 2.5 and 4.8 µM, respectively. Crotoxin competed with radioactive α-bungarotoxin for binding to Torpedo and human α7 nAChRs and to the acetylcholine binding protein. Pancreatic PLA2 interacted similarly with these targets; moreover, it inhibited radioactive α-bungarotoxin binding to the water-soluble extracellular domain of human α9 nAChR, and blocked acetylcholine induced currents in human α9α10 nAChRs heterologously expressed in Xenopus oocytes. These and our earlier results show that all snake PLA2s, including presynaptically active crotoxin and ß-bungarotoxin, as well as mammalian pancreatic PLA2, interact with nAChRs. The data obtained suggest that this interaction may be a general property of all PLA2s, which should be proved by further experiments.
[Mh] Termos MeSH primário: Neurônios/fisiologia
Pâncreas/enzimologia
Fosfolipases A2/farmacologia
Venenos de Serpentes/enzimologia
[Mh] Termos MeSH secundário: Acetilcolina/metabolismo
Animais
Bungarotoxinas/farmacologia
Crotoxina/farmacologia
Seres Humanos
Lymnaea/citologia
Neurônios/efeitos dos fármacos
Receptores Nicotínicos/metabolismo
Suínos/metabolismo
Xenopus laevis/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bungarotoxins); 0 (Receptors, Nicotinic); 0 (Snake Venoms); 9007-40-3 (Crotoxin); EC 3.1.1.4 (Phospholipases A2); N9YNS0M02X (Acetylcholine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171013
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0186206


  10 / 13581 MEDLINE  
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[PMID]:28965946
[Au] Autor:Shintani T; Sakoguchi H; Yoshihara A; Izumori K; Sato M
[Ad] Endereço:Research & Development, Matsutani Chemical Industry Co Ltd, Itami, Hyogo 664-8508, Japan.
[Ti] Título:d-Allulose, a stereoisomer of d-fructose, extends Caenorhabditis elegans lifespan through a dietary restriction mechanism: A new candidate dietary restriction mimetic.
[So] Source:Biochem Biophys Res Commun;493(4):1528-1533, 2017 Dec 02.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Dietary restriction (DR) is an effective intervention known to increase lifespan in a wide variety of organisms. DR also delays the onset of aging-associated diseases. DR mimetics, compounds that can mimic the effects of DR, have been intensively explored. d-Allulose (d-Alu), the C3-epimer of d-fructose, is a rare sugar that has various health benefits, including anti-hyperglycemia and anti-obesity effects. Here, we report that d-Alu increased the lifespan of Caenorhabditis elegans both under monoxenic and axenic culture conditions. d-Alu did not further extend the lifespan of the long-lived DR model eat-2 mutant, strongly indicating that the effect is related to DR. However, d-Alu did not reduce the food intake of wild-type C. elegans. To explore the mechanisms of the d-Alu longevity effect, we examined the lifespan of d-Alu-treated mutants deficient for nutrient sensing pathway-related genes daf-16, sir-2.1, aak-2, and skn-1. As a result, d-Alu increased the lifespan of the daf-16, sir-2.1, and skn-1 mutants, but not the aak-2 mutant, indicating that the lifespan extension was dependent on the energy sensor, AMP-activated protein kinase (AMPK). d-Alu also enhanced the mRNA expression and enzyme activities of superoxide dismutase (SOD) and catalase. From these findings, we conclude that d-Alu extends lifespan by increasing oxidative stress resistance through a DR mechanism, making it a candidate DR mimetic.
[Mh] Termos MeSH primário: Caenorhabditis elegans/efeitos dos fármacos
Restrição Calórica/métodos
Frutose/farmacologia
[Mh] Termos MeSH secundário: Proteínas Quinases Ativadas por AMP/metabolismo
Animais
Materiais Biomiméticos/química
Materiais Biomiméticos/farmacologia
Caenorhabditis elegans/genética
Caenorhabditis elegans/fisiologia
Proteínas de Caenorhabditis elegans/genética
Proteínas de Caenorhabditis elegans/metabolismo
Catalase/genética
Catalase/metabolismo
Ingestão de Alimentos/efeitos dos fármacos
Ingestão de Alimentos/genética
Ingestão de Alimentos/fisiologia
Frutose/química
Genes de Helmintos
Longevidade/efeitos dos fármacos
Longevidade/genética
Longevidade/fisiologia
Mutação
Estresse Oxidativo/efeitos dos fármacos
Proteínas Serina-Treonina Quinases/genética
Proteínas Serina-Treonina Quinases/metabolismo
Receptores Nicotínicos/genética
Receptores Nicotínicos/metabolismo
Estereoisomerismo
Superóxido Dismutase/genética
Superóxido Dismutase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Caenorhabditis elegans Proteins); 0 (Eat-2 protein, C elegans); 0 (Receptors, Nicotinic); 23140-52-5 (psicose); 30237-26-4 (Fructose); EC 1.11.1.6 (Catalase); EC 1.15.1.1 (Superoxide Dismutase); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.31 (AAK-2 protein, C elegans); EC 2.7.11.31 (AMP-Activated Protein Kinases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171003
[St] Status:MEDLINE



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