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1.
Front Mol Biosci ; 11: 1390711, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38737334

RESUMO

Despite an array of hypothesised implications for health, disease, and therapeutic development, antibodies against the non-human sialic acid N-glycolylneuraminic acid (Neu5Gc) remain a subject of much debate. This systematic review of 114 publications aimed to generate a comprehensive overview of published studies in this field, addressing both the reported prevalence of anti-Neu5Gc antibodies in the human population and whether experimental variation accounts for the conflicting reports about the extent of this response. Absolute titres of anti-Neu5Gc antibodies, the reported prevalence of these antibodies, and the individual variation observed within experiments were analysed and grouped according to biological context ('inflammation', 'xenotransplantation', 'biotherapeutic use', 'cancer', and 'healthy populations'), detection method, target epitope selection, and choice of blocking agent. These analyses revealed that the experimental method had a notable impact on both the reported prevalence and absolute titres of anti-Neu5Gc antibodies in the general population, thereby limiting the ability to ascribe reported trends to genuine biological differences or the consequence of experimental design. Overall, this review highlights important knowledge gaps in the study of antibodies against this important xenoautoantigen and the need to establish a standardised method for their quantification if the extent of the importance of Neu5Gc in human health is to be fully understood.

2.
RSC Adv ; 14(6): 3723-3729, 2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38268544

RESUMO

Novel methods to construct small molecule-protein bioconjugates are integral to the development of new biomedicines for a variety of diseases. C-C linked bioconjugates are increasingly desirable in this application due to their in vivo stability and can be accessed through cross aldol bioconjugation of reactive α-oxo aldehyde handles easily introduced at the N-terminus of proteins by periodate oxidation. We previously developed an organocatalyst-mediated protein aldol ligation (OPAL) for chemical modification of these reactive aldehydes, but the efficiency of this method was limited when a proline residue was directly adjacent to the N-terminus due to intramolecular hemiaminal formation. Herein we explore the competition between this cyclisation and the OPAL modification and demonstrate bioconjugation can be favoured through use of acidic pH for both oxidation and OPAL, and optimisation of reaction conditions and organocatalyst. We then showcase the utility of this acidic-OPAL in modification of the cholera toxin B-subunit (CTB), a homo-pentameric protein of biomedical promise.

3.
J Clin Pathol ; 76(8): 561-565, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36894313

RESUMO

Diffuse alveolar damage (DAD) is the histological expression of acute respiratory distress syndrome and characterises lung pathology due to infection with SARS-CoV-2, and other respiratory pathogens of clinical significance. DAD reflects a time-dependent immunopathological process, progressing from an early/exudative stage through to an organising/fibrotic stage, yet within an individual these different stages of DAD may coexist. Understanding the progression of DAD is central to the development of new therapeutics to limit progressive lung damage. Here, we applied highly multiplexed spatial protein profiling to autopsy lung tissues derived from 27 patients who died from COVID-19 and identified a protein signature (ARG1, CD127, GZMB, IDO1, Ki67, phospho-PRAS40 (T246) and VISTA) that distinguishes early DAD from late DAD with good predictive accuracy. These proteins warrant further investigation as potential regulators of DAD progression.


Assuntos
COVID-19 , Síndrome do Desconforto Respiratório , Humanos , COVID-19/diagnóstico , COVID-19/patologia , SARS-CoV-2 , Pulmão/patologia , Síndrome do Desconforto Respiratório/patologia , Autopsia
4.
Org Lett ; 25(12): 2001-2005, 2023 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-36662590

RESUMO

α-Formylglycine (fGly) is a rare residue located in the active site of sulfatases and serves as a precursor to pharmaceutically relevant motifs. The installation of fGly motifs into peptides is currently challenging due to degradation under the acidic and nucleophile-rich conditions accompanying resin cleavage during solid-phase peptide synthesis. We report the synthesis of acid- and nucleophile-tolerant α-formylglycine building blocks from vitamin C and use them to prepare callyaerin A, a macrocyclic peptide containing an fGly-derived motif.


Assuntos
Alanina , Técnicas de Síntese em Fase Sólida , Alanina/química , Glicina/química , Sulfatases/química , Sulfatases/metabolismo , Peptídeos/química
5.
iScience ; 25(12): 105675, 2022 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-36561885

RESUMO

The ability of tumors to establish a pro-tumorigenic microenvironment is an important point of investigation in the search for new therapeutics. Tumors form microenvironments in part by the "education" of immune cells attracted via chemotactic axes such as that of CCR5-CCL5. Further, CCR5 upregulation by cancer cells, coupled with its association with pro-tumorigenic features such as drug resistance and metastasis, has suggested CCR5 as a therapeutic target. However, with several conformational "pools" being reported, phenotypic investigations must be capable of unveiling conformational heterogeneity. Addressing this challenge, we performed super-resolution structured illumination microscopy (SIM) and single molecule partially TIRF-coupled HILO (PaTCH) microscopy of CCR5 in fixed cells. SIM data revealed a non-random spatial distribution of CCR5 assemblies, while Intensity-tracking of CCR5 assemblies from PaTCH images indicated dimeric sub-units independent of CCL5 perturbation. These biophysical methods can provide important insights into the structure and function of onco-immunogenic receptors and many other biomolecules.

6.
iScience ; 25(1): 103672, 2022 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-34957382

RESUMO

Inflammatory cytokines and chemokines (CC) drive COVID-19 pathology. Yet, patients with similar circulating CC levels present with different disease severity. Here, we determined 171 microRNAomes from 58 hospitalized COVID-19 patients (Cohort 1) and levels of 25 cytokines and chemokines (CC) in the same samples. Combining microRNA (miRNA) and CC measurements allowed for discrimination of severe cases with greater accuracy than using miRNA or CC levels alone. Severity group-specific associations between miRNAs and COVID-19-associated CC (e.g., IL6, CCL20) or clinical hallmarks of COVID-19 (e.g., neutrophilia, hypoalbuminemia) separated patients with similar CC levels but different disease severity. Analysis of an independent cohort of 108 patients from a different center (Cohort 2) demonstrated feasibility of CC/miRNA profiling in leftover hospital blood samples with similar severe disease CC and miRNA profiles, and revealed CCL20, IL6, IL10, and miR-451a as key correlates of fatal COVID-19. These findings highlight that systemic miRNA/CC networks underpin severe COVID-19.

7.
ACS Chem Biol ; 16(11): 2387-2400, 2021 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-34751550

RESUMO

Site-selective chemical methods for protein bioconjugation have revolutionized the fields of cell and chemical biology through the development of novel protein/enzyme probes bearing fluorescent, spectroscopic, or even toxic cargos. Herein, we report two new methods for the bioconjugation of α-oxo aldehyde handles within proteins using small molecule aniline and/or phenol probes. The "α-oxo-Mannich" and "catalyst-free aldol" ligations both compete for the electrophilic α-oxo aldehyde, which displays pH divergent reactivity proceeding through the "Mannich" pathway at acidic pH to afford bifunctionalized bioconjugates, and the "catalyst-free aldol" pathway at neutral pH to afford monofunctionalized bioconjugates. We explore the substrate scope and utility of both of these bioconjugations in the construction of neoglycoproteins, in the process formulating a mechanistic rationale for how both pathways intersect with each other at different reaction pH's.


Assuntos
Aldeídos/química , Bases de Mannich/química , Proteínas/química , Compostos de Anilina/química , Catálise , Concentração de Íons de Hidrogênio , Peptídeos/química
8.
Sci Rep ; 8(1): 8003, 2018 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-29789661

RESUMO

Cell-to-cell communication engages signaling and spatiotemporal reorganization events driven by highly context-dependent and dynamic intercellular interactions, which are difficult to capture within heterogeneous primary cell cultures. Here, we present a straightforward correlative imaging approach utilizing commonly available instrumentation to sample large numbers of cell-cell interaction events, allowing qualitative and quantitative characterization of rare functioning cell-conjugates based on calcium signals. We applied this approach to examine a previously uncharacterized immunological synapse, investigating autologous human blood CD4+ T cells and monocyte-derived macrophages (MDMs) forming functional conjugates in vitro. Populations of signaling conjugates were visualized, tracked and analyzed by combining live imaging, calcium recording and multivariate statistical analysis. Correlative immunofluorescence was added to quantify endogenous molecular recruitments at the cell-cell junction. By analyzing a large number of rare conjugates, we were able to define calcium signatures associated with different states of CD4+ T cell-MDM interactions. Quantitative image analysis of immunostained conjugates detected the propensity of endogenous T cell surface markers and intracellular organelles to polarize towards cell-cell junctions with high and sustained calcium signaling profiles, hence defining immunological synapses. Overall, we developed a broadly applicable approach enabling detailed single cell- and population-based investigations of rare cell-cell communication events with primary cells.


Assuntos
Linfócitos T CD4-Positivos/fisiologia , Comunicação Celular/fisiologia , Sinapses Imunológicas/fisiologia , Macrófagos/fisiologia , Imagem Molecular/métodos , Análise de Célula Única/instrumentação , Células Apresentadoras de Antígenos/citologia , Células Apresentadoras de Antígenos/fisiologia , Linfócitos T CD4-Positivos/citologia , Comunicação Celular/imunologia , Células Cultivadas , Estudos de Avaliação como Assunto , Humanos , Macrófagos/citologia , Imagem Molecular/estatística & dados numéricos , Análise de Componente Principal , Transdução de Sinais/imunologia , Análise de Célula Única/métodos , Gravação em Vídeo
9.
J Leukoc Biol ; 98(1): 59-71, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25957306

RESUMO

CCR5 is a chemokine receptor expressed on leukocytes and a coreceptor used by HIV-1 to enter CD4(+) T lymphocytes and macrophages. Stimulation of CCR5 by chemokines triggers internalization of chemokine-bound CCR5 molecules in a process called down-modulation, which contributes to the anti-HIV activity of chemokines. Recent studies have shown that CCR5 conformational heterogeneity influences chemokine-CCR5 interactions and HIV-1 entry in transfected cells or activated CD4(+) T lymphocytes. However, the effect of CCR5 conformations on other cell types and on the process of down-modulation remains unclear. We used mAbs, some already shown to detect distinct CCR5 conformations, to compare the behavior of CCR5 on in vitro generated human T cell blasts, monocytes and MDMs and CHO-CCR5 transfectants. All human cells express distinct antigenic forms of CCR5 not detected on CHO-CCR5 cells. The recognizable populations of CCR5 receptors exhibit different patterns of down-modulation on T lymphocytes compared with myeloid cells. On T cell blasts, CCR5 is recognized by all antibodies and undergoes rapid chemokine-mediated internalization, whereas on monocytes and MDMs, a pool of CCR5 molecules is recognized by a subset of antibodies and is not removed from the cell surface. We demonstrate that this cell surface-retained form of CCR5 responds to prolonged treatment with more-potent chemokine analogs and acts as an HIV-1 coreceptor. Our findings indicate that the regulation of CCR5 is highly specific to cell type and provide a potential explanation for the observation that native chemokines are less-effective HIV-entry inhibitors on macrophages compared with T lymphocytes.


Assuntos
Regulação para Baixo , Células Mieloides/metabolismo , Receptores CCR5/fisiologia , Linfócitos T/metabolismo , Animais , Anticorpos Monoclonais/imunologia , Antígenos/sangue , Células CHO , Cricetinae , Cricetulus , Humanos , Ligantes , Microscopia de Fluorescência , Conformação Proteica , Receptores CCR5/imunologia , Receptores CCR5/metabolismo
10.
Immunology ; 134(3): 246-56, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21977995

RESUMO

Co-ordinated movement and controlled positioning of leucocytes is key to the development, maintenance and proper functioning of the immune system. Chemokines and their receptors play an essential role in these events by mediating directed cell migration, often referred to as chemotaxis. The chemotactic property of these molecules is also thought to contribute to an array of pathologies where inappropriate recruitment of specific chemokine receptor-expressing leucocytes is observed, including cancer and inflammatory diseases. As a result, chemokine receptors have become major targets for therapeutic intervention, and during the past 15 years much research has been devoted to understanding the regulation of their biological activity. From these studies, processes which govern the availability of functional chemokine receptors at the cell surface have emerged as playing a central role. In this review, we summarize and discuss current knowledge on the molecular mechanisms contributing to the regulation of chemokine receptor surface expression, from gene transcription and protein degradation to post-translational modifications, multimerization, intracellular transport and cross-talk.


Assuntos
Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismo , Regulação da Expressão Gênica , Humanos , Modelos Biológicos , Multimerização Proteica , Processamento de Proteína Pós-Traducional , Transporte Proteico , Proteólise , Receptor Cross-Talk , Receptores de Quimiocinas/química
11.
Blood ; 117(6): 1851-60, 2011 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-21148810

RESUMO

During innate immune responses, the inflammatory CC chemokine receptors CCR1, CCR2, and CCR5 mediate the recruitment of blood monocytes to infected tissues by promoting cell migration in response to chemokines CCL2-5. Toll-like receptors also play an essential role, allowing pathogen recognition by the recruited monocytes. Here, we demonstrate that Toll-like receptor 2 (TLR2) stimulation by lipoteichoic acid (LTA) from Staphylococcus aureus leads to gradual down-modulation of CCR1, CCR2, and CCR5 from the plasma membrane of human blood-isolated monocytes and inhibits chemotaxis. Interestingly, LTA does not promote rapid desensitization of chemokine-mediated calcium responses. We found that the TLR2 crosstalk with chemokine receptors is not dependent on the Toll/interleukin-1 receptor domain-containing adaptor protein, but instead involves phospholipase C, the small G protein Rac1, and is phorbol ester sensitive. Activation of this pathway by LTA lead to ß-arrestin-mediated endocytosis of Ser349-phosphorylated CCR5 into recycling endosomes, as does CCL5 treatment. However, LTA-induced internalization of CCR5 is a slower process associated with phospholipase C-mediated and phorbol ester-sensitive phosphorylation. Overall, our data indicate that TLR2 negatively regulates CCR1, CCR2, and CCR5 on human blood monocytes by activating the machinery used to support chemokine-dependent down-modulation and provide a molecular mechanism for inhibiting monocyte migration after pathogen recognition.


Assuntos
Monócitos/imunologia , Receptores CCR1/sangue , Receptores CCR2/sangue , Receptores CCR5/sangue , Receptor 2 Toll-Like/sangue , Sinalização do Cálcio/efeitos dos fármacos , Movimento Celular/imunologia , Quimiotaxia de Leucócito , Regulação para Baixo/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Técnicas In Vitro , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/farmacologia , Monócitos/efeitos dos fármacos , Monócitos/fisiologia , Fosforilação , Receptor Cross-Talk/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Staphylococcus aureus/imunologia , Ácidos Teicoicos/imunologia , Ácidos Teicoicos/farmacologia
12.
PLoS Pathog ; 6(3): e1000813, 2010 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-20300600

RESUMO

Highly phagocytic macrophages line the marginal zone (MZ) of the spleen and the lymph node subcapsular sinus. Although these macrophages have been attributed with a variety of functions, including the uptake and clearance of blood and lymph-borne pathogens, little is known about the effector mechanisms they employ after pathogen uptake. Here, we have combined gene expression profiling and RNAi using a stromal macrophage cell line with in situ analysis of the leishmanicidal activity of marginal zone macrophages (MZM) and marginal metallophilic macrophages (MMM) in wild type and gene targeted mice. Our data demonstrate a critical role for interferon regulatory factor-7 (IRF-7) in regulating the killing of intracellular Leishmania donovani by these specialised splenic macrophage sub-populations. This study, therefore, identifies a new role for IRF-7 as a regulator of innate microbicidal activity against this, and perhaps other, non-viral intracellular pathogens. This study also highlights the importance of selecting appropriate macrophage populations when studying pathogen interactions with this functionally diverse lineage of cells.


Assuntos
Fator Regulador 7 de Interferon/imunologia , Leishmania donovani/imunologia , Leishmaniose Visceral/imunologia , Macrófagos/imunologia , Macrófagos/parasitologia , Animais , Expressão Gênica/imunologia , Fator Regulador 7 de Interferon/genética , Fator Regulador 7 de Interferon/metabolismo , Interferon-alfa/imunologia , Interferon-alfa/metabolismo , Interferon gama/imunologia , Interferon gama/metabolismo , Macrófagos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , Fagossomos/imunologia , RNA Interferente Pequeno , Baço/imunologia , Baço/parasitologia
13.
Methods Enzymol ; 460: 357-77, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19446735

RESUMO

Chemokine receptors are G protein-coupled receptors (GPCRs) that, through their ability to regulate chemotaxis by responding to small chemoattractant peptides termed chemokines, are involved in the development, maintenance, and functional activities of the immune system. In addition, members of the chemokine receptor family have been implicated in a number of other physiological and pathological processes, including human immunodeficiency virus infection and malaria. These activities are dependent on receptor expression at the cell surface and cellular events that reduce the cell-surface expression of chemokine receptors can abrogate these activities. Moreover, internalization of chemokine receptors by endocytosis is necessary for both receptor degradation and recycling, key regulatory processes that determine cell-surface expression levels. Here we provide detailed methods for the quantitative analysis of CCR5 endocytosis and recycling by flow cytometry, as well as fluorescence and electron microscopic procedures to analyze the endocytosis and intracellular trafficking of CCR5 by immunolabeling of cells or cryosections. In principle, the same approaches can be used for analyzing other chemokine receptors and other GPCR or non-GPCR cell-surface proteins.


Assuntos
Endocitose/fisiologia , Transporte Proteico/fisiologia , Receptores de Quimiocinas/metabolismo , Animais , Western Blotting , Células CHO , Cricetinae , Cricetulus , Citometria de Fluxo , Humanos , Microscopia Eletrônica , Microscopia de Fluorescência , Transporte Proteico/genética , Receptores de Quimiocinas/genética
14.
J Cell Sci ; 118(Pt 22): 5279-89, 2005 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-16263761

RESUMO

Dishevelled family proteins are multidomain intracellular transducers of Wnt signals. Ectopically expressed mammalian Dishevelled 2 (Dvl-2) activates downstream signalling and localises to cytoplasmic puncta. It has been suggested that these Dvl-2-containing structures correspond to intracellular vesicles and may be involved in the Wnt signal transduction process. We report that cytoplasmic puncta are primarily formed in cells expressing Dvl-2 at high levels. Lower levels of expression can activate signalling without forming puncta. The structures do not localise with markers of the early or late endocytic pathway and time-lapse analysis demonstrates that Dvl-2 puncta move in a random fashion over short distances but do not originate from the plasma membrane. Based on our findings, we propose that Dvl-2 puncta are protein aggregates that are not required for signalling.


Assuntos
Citoplasma/metabolismo , Fosfoproteínas/metabolismo , Transdução de Sinais , Proteínas Wnt/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , Antígenos CD/metabolismo , Biomarcadores/análise , Cricetinae , Proteínas Desgrenhadas , Cães , Endocitose , Retículo Endoplasmático/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Fosfoproteínas/química , Fosfoproteínas/genética , Glicoproteínas da Membrana de Plaquetas/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Transporte Proteico , Transdução de Sinais/efeitos dos fármacos , Tetraspanina 30 , Fatores de Tempo , Transfecção , Proteínas de Transporte Vesicular
15.
Mol Biol Cell ; 16(2): 902-17, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15591129

RESUMO

The signaling activity of several chemokine receptors, including CC chemokine receptor 5 (CCR5), is in part controlled by their internalization, recycling, and/or degradation. For CCR5, agonists such as the chemokine CCL5 induce internalization into early endosomes containing the transferrin receptor, a marker for clathrin-dependent endocytosis, but it has been suggested that CCR5 may also follow clathrin-independent routes of internalization. Here, we present a detailed analysis of the role of clathrin in chemokine-induced CCR5 internalization. Using CCR5-transfected cell lines, immunofluorescence, and electron microscopy, we demonstrate that CCL5 causes the rapid redistribution of scattered cell surface CCR5 into large clusters that are associated with flat clathrin lattices. Invaginated clathrin-coated pits could be seen at the edge of these lattices and, in CCL5-treated cells, these pits contain CCR5. Receptors internalized via clathrin-coated vesicles follow the clathrin-mediated endocytic pathway, and depletion of clathrin with small interfering RNAs inhibits CCL5-induced CCR5 internalization. We found no evidence for CCR5 association with caveolae during agonist-induced internalization. However, sequestration of cholesterol with filipin interferes with agonist binding to CCR5, suggesting that cholesterol and/or lipid raft domains play some role in the events required for CCR5 activation before internalization.


Assuntos
Clatrina/metabolismo , Endocitose/efeitos dos fármacos , Receptores CCR5/agonistas , Receptores CCR5/metabolismo , Animais , Antibacterianos/farmacologia , Células CHO , Linhagem Celular , Quimiocina CCL4 , Quimiocinas CC/metabolismo , Clatrina/ultraestrutura , Cricetinae , Cricetulus , Células Endoteliais/ultraestrutura , Células Epiteliais/ultraestrutura , Filipina/farmacologia , Técnica Indireta de Fluorescência para Anticorpo , Corantes Fluorescentes , Proteínas de Fluorescência Verde/metabolismo , Hidrazinas , Pulmão/citologia , Proteínas Inflamatórias de Macrófagos/metabolismo , Mastócitos/citologia , Mastócitos/ultraestrutura , Microscopia Confocal , Vison , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ratos , Receptores CCR5/ultraestrutura
16.
Traffic ; 5(7): 529-43, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15180829

RESUMO

Following agonist activation, the chemokine receptor CCR5 is internalised through clathrin-coated pits and delivered to recycling endosomes. Subsequently, ligand- free and resensitised receptors are recycled to the cell surface. Currently little is known of the mechanisms regulating resensitisation and recycling of this G-protein coupled receptor. Here we show that raising the pH of endocytic compartments, using bafilomycin A, monensin or NH(4)Cl, does not significantly affect CCR5 endocytosis, recycling or dephosphorylation. By contrast, these reagents inhibited recycling of another well-characterised G protein coupled receptor, the beta(2)-adrenergic receptor, following agonist-induced internalisation. CCR5-bound RANTES (CCL5) and MIP-1beta (CCL4) only exhibit pH-dependent dissociation at pH < 4.0, below the values normally found in endocytic organelles. Although receptor-agonist dissociation is not dependent on low pH, the subsequent degradation of released chemokine is inhibited in the presence of reagents that raise endosomal pH. Our data show that exposure to low pH is not required for RANTES or MIP-1beta dissociation from CCR5, or for recycling of internalised CCR5 to the cell surface.


Assuntos
Receptores CCR5/química , Animais , Células CHO , Membrana Celular/metabolismo , Separação Celular , Quimiocina CCL5/farmacologia , Vesículas Revestidas por Clatrina/metabolismo , Cricetinae , Endocitose , Endossomos/metabolismo , Citometria de Fluxo , Proteínas de Fluorescência Verde/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Imunoprecipitação , Ligantes , Macrolídeos/farmacologia , Camundongos , Microscopia de Fluorescência , Monensin/química , Fosforilação , Ligação Proteica , Receptores Adrenérgicos beta 2/metabolismo , Receptores Acoplados a Proteínas G , Fatores de Tempo
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