Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 38
Filtrar
1.
Mol Cell ; 77(3): 488-500.e9, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-31761495

RESUMO

Pioneer transcription factors (pTFs) bind to target sites within compact chromatin, initiating chromatin remodeling and controlling the recruitment of downstream factors. The mechanisms by which pTFs overcome the chromatin barrier are not well understood. Here, we reveal, using single-molecule fluorescence, how the yeast transcription factor Rap1 invades and remodels chromatin. Using a reconstituted chromatin system replicating yeast promoter architecture, we demonstrate that Rap1 can bind nucleosomal DNA within a chromatin fiber but with shortened dwell times compared to naked DNA. Moreover, we show that Rap1 binding opens chromatin fiber structure by inhibiting inter-nucleosome contacts. Finally, we reveal that Rap1 collaborates with the chromatin remodeler RSC to displace promoter nucleosomes, paving the way for long-lived bound states on newly exposed DNA. Together, our results provide a mechanistic view of how Rap1 gains access and opens chromatin, thereby establishing an active promoter architecture and controlling gene expression.


Assuntos
Cromatina/metabolismo , Nucleossomos/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas de Ligação a Telômeros/metabolismo , Fatores de Transcrição/metabolismo , Cromatina/genética , Montagem e Desmontagem da Cromatina , DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica/genética , Nucleossomos/metabolismo , Nucleossomos/fisiologia , Regiões Promotoras Genéticas/genética , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Complexo Shelterina , Proteínas de Ligação a Telômeros/genética , Fatores de Transcrição/genética
2.
Nature ; 587(7835): 668-672, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32911482

RESUMO

The DNA sensor cyclic GMP-AMP synthase (cGAS) initiates innate immune responses following microbial infection, cellular stress and cancer1. Upon activation by double-stranded DNA, cytosolic cGAS produces 2'3' cGMP-AMP, which triggers the induction of inflammatory cytokines and type I interferons 2-7. cGAS is also present inside the cell nucleus, which is replete with genomic DNA8, where chromatin has been implicated in restricting its enzymatic activity9. However, the structural basis for inhibition of cGAS by chromatin remains unknown. Here we present the cryo-electron microscopy structure of human cGAS bound to nucleosomes. cGAS makes extensive contacts with both the acidic patch of the histone H2A-H2B heterodimer and nucleosomal DNA. The structural and complementary biochemical analysis also find cGAS engaged to a second nucleosome in trans. Mechanistically, binding of the nucleosome locks cGAS into a monomeric state, in which steric hindrance suppresses spurious activation by genomic DNA. We find that mutations to the cGAS-acidic patch interface are sufficient to abolish the inhibitory effect of nucleosomes in vitro and to unleash the activity of cGAS on genomic DNA in living cells. Our work uncovers the structural basis of the interaction between cGAS and chromatin and details a mechanism that permits self-non-self discrimination of genomic DNA by cGAS.


Assuntos
Microscopia Crioeletrônica , Nucleossomos/metabolismo , Nucleotidiltransferases/antagonistas & inibidores , Nucleotidiltransferases/química , Células HeLa , Histonas/metabolismo , Humanos , Modelos Moleculares , Mutação , Nucleossomos/química , Nucleossomos/ultraestrutura , Nucleotidiltransferases/metabolismo , Nucleotidiltransferases/ultraestrutura
3.
Pharmacol Rev ; 73(1): 310-520, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33370241

RESUMO

5-HT receptors expressed throughout the human body are targets for established therapeutics and various drugs in development. Their diversity of structure and function reflects the important role 5-HT receptors play in physiologic and pathophysiological processes. The present review offers a framework for the official receptor nomenclature and a detailed understanding of each of the 14 5-HT receptor subtypes, their roles in the systems of the body, and, where appropriate, the (potential) utility of therapeutics targeting these receptors. SIGNIFICANCE STATEMENT: This review provides a comprehensive account of the classification and function of 5-hydroxytryptamine receptors, including how they are targeted for therapeutic benefit.


Assuntos
Farmacologia Clínica , Serotonina , Humanos , Ligantes , Receptores de Serotonina
4.
Nature ; 512(7514): 276-81, 2014 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-25119048

RESUMO

Neurotransmitter-gated ion channels of the Cys-loop receptor family mediate fast neurotransmission throughout the nervous system. The molecular processes of neurotransmitter binding, subsequent opening of the ion channel and ion permeation remain poorly understood. Here we present the X-ray structure of a mammalian Cys-loop receptor, the mouse serotonin 5-HT3 receptor, at 3.5 Å resolution. The structure of the proteolysed receptor, made up of two fragments and comprising part of the intracellular domain, was determined in complex with stabilizing nanobodies. The extracellular domain reveals the detailed anatomy of the neurotransmitter binding site capped by a nanobody. The membrane domain delimits an aqueous pore with a 4.6 Å constriction. In the intracellular domain, a bundle of five intracellular helices creates a closed vestibule where lateral portals are obstructed by loops. This 5-HT3 receptor structure, revealing part of the intracellular domain, expands the structural basis for understanding the operating mechanism of mammalian Cys-loop receptors.


Assuntos
Receptores 5-HT3 de Serotonina/química , Sequência de Aminoácidos , Animais , Sítios de Ligação , Cristalografia por Raios X , Camundongos , Modelos Moleculares , Dados de Sequência Molecular , Neurotransmissores/metabolismo , Estrutura Quaternária de Proteína , Estrutura Terciária de Proteína , Subunidades Proteicas/química , Subunidades Proteicas/metabolismo , Receptores 5-HT3 de Serotonina/metabolismo
5.
Angew Chem Int Ed Engl ; 58(8): 2341-2344, 2019 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-30569539

RESUMO

Optical monitoring of neuronal voltage using fluorescent indicators is a powerful approach for the interrogation of the cellular and molecular logic of the nervous system. Herein, a semisynthetic tethered voltage indicator (STeVI1) based upon nile red is described that displays voltage sensitivity when genetically targeted to neuronal membranes. This environmentally sensitive probe allows for wash-free imaging and faithfully detects supra- and sub-threshold activity in neurons.


Assuntos
Corantes Fluorescentes/química , Neurônios/metabolismo , Imagem Óptica , Oxazinas/química , Células HEK293 , Humanos , Estrutura Molecular , Neurônios/citologia
6.
J Am Chem Soc ; 140(13): 4517-4521, 2018 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-29336153

RESUMO

The development of thermostable and solvent-tolerant metalloproteins is a long-sought goal for many applications in synthetic biology and biotechnology. In this work, we were able to engineer a highly thermostable and organic solvent-stable metallo variant of the B1 domain of protein G (GB1) with a tetrahedral zinc binding site reminiscent of the one of thermolysin. Promising candidates were designed computationally by applying a protocol based on classical and first-principles molecular dynamics simulations in combination with genetic algorithm optimization. The most promising of the computationally predicted mutants was expressed and structurally characterized and yielded a highly thermostable protein. The experimental results thus confirm the predictive power of the applied computational protein engineering approach for the de novo design of highly stable metalloproteins.


Assuntos
Algoritmos , Metaloproteínas/química , Metaloproteínas/genética , Estabilidade Enzimática , Engenharia de Proteínas , Temperatura
7.
J Biol Chem ; 291(2): 652-7, 2016 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-26565027

RESUMO

Tryptophan metabolites in the kynurenine pathway are up-regulated by pro-inflammatory cytokines or glucocorticoids, and are linked to anti-inflammatory and immunosuppressive activities. In addition, they are up-regulated in pathologies such as cancer, autoimmune diseases, and psychiatric disorders. The molecular mechanisms of how kynurenine pathway metabolites cause these effects are incompletely understood. On the other hand, pro-inflammatory cytokines also up-regulate the amounts of tetrahydrobiopterin (BH4), an enzyme cofactor essential for the synthesis of several neurotransmitter and nitric oxide species. Here we show that xanthurenic acid is a potent inhibitor of sepiapterin reductase (SPR), the final enzyme in de novo BH4 synthesis. The crystal structure of xanthurenic acid bound to the active site of SPR reveals why among all kynurenine pathway metabolites xanthurenic acid is the most potent SPR inhibitor. Our findings suggest that increased xanthurenic acid levels resulting from up-regulation of the kynurenine pathway could attenuate BH4 biosynthesis and BH4-dependent enzymatic reactions, linking two major metabolic pathways known to be highly up-regulated in inflammation.


Assuntos
Biopterinas/análogos & derivados , Cinurenina/metabolismo , Redes e Vias Metabólicas , Xanturenatos/metabolismo , Animais , Biopterinas/biossíntese , Biopterinas/química , Calorimetria , Cristalografia por Raios X , Humanos , Concentração Inibidora 50 , Cinurenina/química , Camundongos , Modelos Moleculares , Ratos , Ressonância de Plasmônio de Superfície , Termodinâmica
8.
Small ; 11(22): 2607-13, 2015 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-25641862

RESUMO

A micrometer-sized affinity bead (red) is (i) taken up into a cell by phagocytosis, (ii) photochemically released from phagosomes, (iii) optically trapped by the cell, and (iv) isolated by cell lysis for subsequent analysis of captured intracellular analyte (green).


Assuntos
Separação Celular/métodos , Citometria de Fluxo/métodos , Imunoensaio/métodos , Microfluídica/métodos , Pinças Ópticas , Células HEK293 , Humanos
9.
J Cell Biol ; 222(3)2023 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-36571579

RESUMO

Functional membrane proteins in the plasma membrane are suggested to have specific membrane environments that play important roles to maintain and regulate their function. However, the local membrane environments of membrane proteins remain largely unexplored due to the lack of available techniques. We have developed a method to probe the local membrane environment surrounding membrane proteins in the plasma membrane by covalently tethering a solvatochromic, environment-sensitive dye, Nile Red, to a GPI-anchored protein and the insulin receptor through a flexible linker. The fluidity of the membrane environment of the GPI-anchored protein depended upon the saturation of the acyl chains of the lipid anchor. The local environment of the insulin receptor was distinct from the average plasma membrane fluidity and was quite dynamic and heterogeneous. Upon addition of insulin, the local membrane environment surrounding the receptor specifically increased in fluidity in an insulin receptor-kinase dependent manner and on the distance between the dye and the receptor.


Assuntos
Membrana Celular , Proteínas de Membrana , Receptor de Insulina , Membrana Celular/metabolismo , Glicosilfosfatidilinositóis/metabolismo , Proteínas Ligadas por GPI/metabolismo , Proteínas de Membrana/metabolismo , Receptor de Insulina/metabolismo , Técnicas de Sonda Molecular
10.
J Biol Chem ; 286(1): 363-9, 2011 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-20978122

RESUMO

Nicotinic acetylcholine receptors (nAChR) in muscle fibers are densely packed in the postsynaptic region at the neuromuscular junction. Rapsyn plays a central role in directing and clustering nAChR during cellular differentiation and neuromuscular junction formation; however, it has not been demonstrated whether rapsyn is the only cause of receptor immobilization. Here, we used single-molecule tracking methods to investigate nAChR mobility in plasma membranes of myoblast cells during their differentiation to myotubes in the presence and absence of rapsyn. We found that in myoblasts the majority of nAChR were immobile and that ∼20% of the receptors showed restricted diffusion in small domains of ∼50 nm. In myoblasts devoid of rapsyn, the fraction of mobile nAChR was considerably increased, accompanied by a 3-fold decrease in the immobile population of nAChR with respect to rapsyn-expressing cells. Half of the mobile receptors were confined to domains of ∼120 nm. Measurements performed in heterologously transfected HEK cells confirmed the direct immobilization of nAChR by rapsyn. However, irrespective of the presence of rapsyn, about one-third of nAChR were confined in 300-nm domains. Our results show (i) that rapsyn efficiently immobilizes nAChR independently of other postsynaptic scaffold components; (ii) nAChR is constrained in confined membrane domains independently of rapsyn; and (iii) in the presence of rapsyn, the size of these domains is strongly reduced.


Assuntos
Membrana Celular/metabolismo , Células Musculares/citologia , Células Musculares/metabolismo , Proteínas Musculares/metabolismo , Receptores Nicotínicos/química , Receptores Nicotínicos/metabolismo , Animais , Diferenciação Celular , Conotoxinas/metabolismo , Difusão , Corantes Fluorescentes/metabolismo , Células HEK293 , Humanos , Camundongos , Movimento , Proteínas Musculares/deficiência , Estrutura Terciária de Proteína
11.
J Am Chem Soc ; 133(42): 16868-74, 2011 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-21910424

RESUMO

G-protein-coupled receptors (GPCRs) are ubiquitous mediators of signal transduction across cell membranes and constitute a very important class of therapeutic targets. In order to study the complex biochemical signaling network coupling to the intracellular side of GPCRs, it is necessary to engineer and control the downstream signaling components, which is difficult to realize in living cells. We have developed a bioanalytical platform enabling the study of GPCRs in their native membrane transferred inside-out from live cells to lectin-coated beads, with both membrane sides of the receptor being accessible for molecular interactions. Using heterologously expressed adenosine A(2A) receptor carrying a yellow fluorescent protein, we showed that the tethered membranes comprised fully functional receptors in terms of ligand and G protein binding. The interactions between the different signaling partners during the formation and subsequent dissociation of the ternary signaling complex on single beads could be observed in real time using multicolor fluorescence microscopy. This approach of tethering inside-out native membranes accessible from both sides is straightforward and readily applied to other transmembrane proteins. It represents a generic platform suitable for ensemble as well as single-molecule measurements to investigate signaling processes at plasma membranes.


Assuntos
Membrana Celular/química , Receptores Acoplados a Proteínas G/química , Ligação Competitiva , Membrana Celular/metabolismo , Células HEK293 , Humanos , Proteínas Imobilizadas/química , Proteínas Imobilizadas/metabolismo , Ligantes , Porosidade , Receptores Acoplados a Proteínas G/metabolismo , Propriedades de Superfície
12.
13.
Elife ; 92020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33320087

RESUMO

The inner nuclear membrane is functionalized by diverse transmembrane proteins that associate with nuclear lamins and/or chromatin. When cells enter mitosis, membrane-chromatin contacts must be broken to allow for proper chromosome segregation; yet how this occurs remains ill-understood. Unexpectedly, we observed that an imbalance in the levels of the lamina-associated polypeptide 1 (LAP1), an activator of ER-resident Torsin AAA+-ATPases, causes a failure in membrane removal from mitotic chromatin, accompanied by chromosome segregation errors and changes in post-mitotic nuclear morphology. These defects are dependent on a hitherto unknown chromatin-binding region of LAP1 that we have delineated. LAP1-induced NE abnormalities are efficiently suppressed by expression of wild-type but not ATPase-deficient Torsins. Furthermore, a dominant-negative Torsin induces chromosome segregation defects in a LAP1-dependent manner. These results indicate that association of LAP1 with chromatin in the nucleus can be modulated by Torsins in the perinuclear space, shedding new light on the LAP1-Torsin interplay.


Assuntos
Cromatina/metabolismo , Segregação de Cromossomos/fisiologia , Proteínas de Choque Térmico HSC70/metabolismo , Mitose/fisiologia , Chaperonas Moleculares/metabolismo , Adenosina Trifosfatases/metabolismo , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Técnicas de Inativação de Genes , Células HCT116 , Proteínas de Choque Térmico HSC70/genética , Células HeLa , Células Hep G2 , Humanos , Chaperonas Moleculares/genética , Membrana Nuclear/metabolismo
14.
Biochim Biophys Acta ; 1768(1): 76-89, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16956576

RESUMO

The nicotinic acetylcholine receptor (nAChR) is a ligand-gated ion channel that switches upon activation from a closed state to a full conducting state. We found that the mutation delta S268K, located at 12' position of the second transmembrane domain of the delta subunit of the human nAChR generates a long-lived intermediate conducting state, from which openings to a wild-type like conductance level occur on a submillisecond time scale. Aiming to understand the interplay between structural changes near the 12' position and channel gating, we investigated the influence of various parameters: different ligands (acetylcholine, choline and epibatidine), ligand concentrations, transmembrane voltages and both fetal and adult nAChRs. Since sojourns in the high conductance state are not fully resolved in time, spectral noise analysis was used as a complement to dwell time analysis to determine the gating rate constants. Open channel current fluctuations are described by a two-state Markov model. The characteristic time of the process is markedly influenced by the ligand and the receptor type, whereas the frequency of openings to the high conductance state increases with membrane hyperpolarization. Conductance changes are discussed with regard to reversible transfer reaction of single protons at the lysine 12' side chain.


Assuntos
Ativação do Canal Iônico , Prótons , Receptores Nicotínicos/metabolismo , Sequência de Aminoácidos , Animais , Linhagem Celular , Colinérgicos/farmacologia , Relação Dose-Resposta a Droga , Humanos , Ativação do Canal Iônico/efeitos dos fármacos , Cinética , Lisina/química , Cadeias de Markov , Potenciais da Membrana/efeitos dos fármacos , Modelos Biológicos , Modelos Moleculares , Dados de Sequência Molecular , Mutação , Técnicas de Patch-Clamp , Conformação Proteica , Subunidades Proteicas/metabolismo , Receptores Nicotínicos/química , Receptores Nicotínicos/efeitos dos fármacos , Receptores Nicotínicos/genética , Torpedo/metabolismo , Transfecção
15.
Nat Biotechnol ; 22(4): 440-4, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15034592

RESUMO

Chemical and biological labeling is fundamental for the elucidation of the function of proteins within biochemical cellular networks. In particular, fluorescent probes allow detection of molecular interactions, mobility and conformational changes of proteins in live cells with high temporal and spatial resolution. We present a generic method to label proteins in vivo selectively, rapidly (seconds) and reversibly, with small molecular probes that can have a wide variety of properties. These probes comprise a chromophore and a metal-ion-chelating nitrilotriacetate (NTA) moiety, which binds reversibly and specifically to engineered oligohistidine sequences in proteins of interest. We demonstrate the feasibility of the approach by binding NTA-chromophore conjugates to a representative ligand-gated ion channel and G protein-coupled receptor, each containing a polyhistidine sequence. We investigated the ionotropic 5HT(3) serotonin receptor by fluorescence measurements to characterize in vivo the probe-receptor interactions, yielding information on structure and plasma membrane distribution of the receptor.


Assuntos
Biotecnologia/métodos , Membrana Celular/metabolismo , Técnicas Genéticas , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Transferência Ressonante de Energia de Fluorescência , Proteínas de Fluorescência Verde , Histidina/química , Humanos , Íons , Cinética , Proteínas Luminescentes/química , Proteínas Luminescentes/metabolismo , Camundongos , Microscopia de Fluorescência , Ácido Nitrilotriacético/química , Ligação Proteica , Fatores de Tempo
16.
ACS Sens ; 2(8): 1191-1197, 2017 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-28766337

RESUMO

We are introducing a new approach to evaluate cellular uptake of drugs and drug candidates into living cells. The approach is based on converting the protein target of a given class of compounds into a fluorescent biosensor. By measuring the binding of different compounds to their cognate biosensor in live cells and comparing these values to those measured in vitro, their cellular uptake and concentrations can be ranked. We demonstrate that our strategy enables the evaluation of the cellular uptake into the cytosol of 2 classes of inhibitors using two different sensor designs; first, sensors comprising the self-labeling protein SNAP conjugated with a chemically modified inhibitor shown for inhibitors of the enzyme human carbonic anhydrase II; and a label-free sensor for inhibitors of protein-protein interactions demonstrated for the protein pair p53-HDM2.

17.
Methods Mol Biol ; 1635: 139-168, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28755368

RESUMO

There is growing interest in the use of mammalian protein expression systems, and in the use of antibody-derived chaperones, for structural studies. Here, we describe protocols ranging from the production of recombinant membrane proteins in stable inducible cell lines to biophysical characterization of purified membrane proteins in complex with llama antibody domains. These protocols were used to solve the structure of the mouse 5-HT3 serotonin receptor but are of broad applicability for crystallization or cryo-electron microscopy projects.


Assuntos
Anticorpos/metabolismo , Receptores 5-HT3 de Serotonina/química , Receptores 5-HT3 de Serotonina/metabolismo , Proteínas Recombinantes/metabolismo , Animais , Camelus , Linhagem Celular , Microscopia Crioeletrônica , Cristalografia por Raios X , Expressão Gênica , Humanos , Proteínas de Membrana/química , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Estabilidade Proteica , Receptores 5-HT3 de Serotonina/genética , Proteínas Recombinantes/química
18.
FEBS Lett ; 580(6): 1654-8, 2006 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-16497304

RESUMO

Fluorescence resonance energy transfer (FRET) is a powerful technique to reveal interactions between membrane proteins in live cells. Fluorescence labeling for FRET is typically performed by fusion with fluorescent proteins (FP) with the drawbacks of a limited choice of fluorophores, an arduous control of donor-acceptor ratio and high background fluorescence arising from intracellular FPs. Here we show that these shortcomings can be overcome by using the acyl carrier protein labeling technique. FRET revealed interactions between cell-surface neurokinin-1 receptors simultaneously labeled with a controlled ratio of donors and acceptors. Moreover, using FRET the specific binding of fluorescent agonists could be monitored.


Assuntos
Proteína de Transporte de Acila/química , Transferência Ressonante de Energia de Fluorescência , Corantes Fluorescentes/química , Mapeamento de Interação de Proteínas/métodos , Receptores Acoplados a Proteínas G/química , Proteína de Transporte de Acila/genética , Carbocianinas/química , Células Cultivadas , Humanos , Proteínas de Membrana/química , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores da Neurocinina-1/química , Receptores da Neurocinina-1/genética , Receptores da Neurocinina-1/metabolismo , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Substância P/química , Substância P/metabolismo , Substância P/farmacologia
20.
Neuron ; 86(6): 1393-406, 2015 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-26087165

RESUMO

Human genetic studies have revealed an association between GTP cyclohydrolase 1 polymorphisms, which decrease tetrahydrobiopterin (BH4) levels, and reduced pain in patients. We now show that excessive BH4 is produced in mice by both axotomized sensory neurons and macrophages infiltrating damaged nerves and inflamed tissue. Constitutive BH4 overproduction in sensory neurons increases pain sensitivity, whereas blocking BH4 production only in these cells reduces nerve injury-induced hypersensitivity without affecting nociceptive pain. To minimize risk of side effects, we targeted sepiapterin reductase (SPR), whose blockade allows minimal BH4 production through the BH4 salvage pathways. Using a structure-based design, we developed a potent SPR inhibitor and show that it reduces pain hypersensitivity effectively with a concomitant decrease in BH4 levels in target tissues, acting both on sensory neurons and macrophages, with no development of tolerance or adverse effects. Finally, we demonstrate that sepiapterin accumulation is a sensitive biomarker for SPR inhibition in vivo.


Assuntos
Biopterinas/análogos & derivados , Regulação da Expressão Gênica/fisiologia , Inflamação/metabolismo , Neuralgia/metabolismo , Oxirredutases do Álcool/metabolismo , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Biopterinas/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Modelos Animais de Doenças , Inibidores Enzimáticos/uso terapêutico , GTP Cicloidrolase/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Transgênicos , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Medição da Dor , Limiar da Dor/efeitos dos fármacos , Limiar da Dor/fisiologia , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/genética , Nervo Isquiático/metabolismo , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo , Sulfassalazina/uso terapêutico , Fatores de Tempo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA