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[PMID]:28455390
[Au] Autor:Christian WV; Hinkle PM
[Ad] Endereço:Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY 14642, U.S.A.
[Ti] Título:Global functions of extracellular, transmembrane and cytoplasmic domains of organic solute transporter ß-subunit.
[So] Source:Biochem J;474(12):1981-1992, 2017 05 25.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Transport of bile acids across the basolateral membrane of the intestinal enterocyte is carried out by the organic solute transporter (Ost) composed of a seven-transmembrane domain (TMD) subunit (Ostα) and an ancillary single TMD subunit (Ostß). Although previous investigations have demonstrated the importance of the TMD of Ostß for its activity, further studies were conducted to assess the contributions of other regions of the Ostß subunit. Transport activity was retained when Ostß was truncated to contain only the TMD with 15 additional residues on each side and co-expressed with Ostα, whereas shorter fragments were inactive. To probe the broader functions of Ostß segments, chimeric proteins were constructed in which N-terminal, TMD or C-terminal regions of Ostß were fused to corresponding regions of receptor activity-modifying protein (RAMP1), a single TMD protein required by several seven-TMD G-protein-coupled receptors including the calcitonin receptor-like receptor (CLR). Ostß/RAMP1 chimeras were expressed with Ostα and CLR. As expected, replacing the Ostß TMD abolished transport activity; however, replacing either the entire N-terminal or entire C-terminal domain of Ostß with RAMP1 sequences did not prevent plasma membrane localization or the ability to support [ H]taurocholate uptake. Co-immunoprecipitation experiments revealed that the C-terminus of Ostß is a previously unrecognized site of interaction with Ostα. All chimeras containing N-terminal RAMP1 segments allowed co-expressed CLR to respond to agonists with strong increases in cyclic AMP. These results provide new insights into the structure and function of the heteromeric Ost transporter complex.
[Mh] Termos MeSH primário: Ácidos e Sais Biliares/metabolismo
Proteínas de Membrana Transportadoras/metabolismo
[Mh] Termos MeSH secundário: Absorção Fisiológica/efeitos dos fármacos
Animais
Transporte Biológico/efeitos dos fármacos
Peptídeo Relacionado com Gene de Calcitonina/genética
Peptídeo Relacionado com Gene de Calcitonina/metabolismo
Proteína Semelhante a Receptor de Calcitonina/agonistas
Proteína Semelhante a Receptor de Calcitonina/genética
Proteína Semelhante a Receptor de Calcitonina/metabolismo
AMP Cíclico/metabolismo
Células HEK293
Seres Humanos
Imunoprecipitação
Proteínas de Membrana Transportadoras/química
Proteínas de Membrana Transportadoras/genética
Camundongos
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/genética
Fragmentos de Peptídeos/metabolismo
Domínios e Motivos de Interação entre Proteínas
Transporte Proteico
Proteína 1 Modificadora da Atividade de Receptores/química
Proteína 1 Modificadora da Atividade de Receptores/genética
Proteína 1 Modificadora da Atividade de Receptores/metabolismo
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
Sistemas do Segundo Mensageiro/efeitos dos fármacos
Homologia Estrutural de Proteína
Ácido Taurocólico/metabolismo
Trítio
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Bile Acids and Salts); 0 (CALCA protein, human); 0 (CALCRL protein, human); 0 (Calcitonin Receptor-Like Protein); 0 (Membrane Transport Proteins); 0 (Peptide Fragments); 0 (Ramp1 protein, mouse); 0 (Receptor Activity-Modifying Protein 1); 0 (Recombinant Fusion Proteins); 0 (organic solute transporter alpha, mouse); 0 (organic solute transporter beta, mouse); 10028-17-8 (Tritium); 5E090O0G3Z (Taurocholic Acid); 83652-28-2 (Calcitonin Gene-Related Peptide); E0399OZS9N (Cyclic AMP)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171217
[Lr] Data última revisão:
171217
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE
[do] DOI:10.1042/BCJ20161093


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[PMID]:29078910
[Au] Autor:Mishima T; Ito Y; Nishizawa N; Amano H; Tsujikawa K; Miyaji K; Watanabe M; Majima M
[Ad] Endereço:Department of Cardiovascular Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
[Ti] Título:RAMP1 signaling improves lymphedema and promotes lymphangiogenesis in mice.
[So] Source:J Surg Res;219:50-60, 2017 Nov.
[Is] ISSN:1095-8673
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Secondary lymphedema commonly arises as a complication of cancer surgery and radiation treatment; however, the underlying mechanisms are poorly understood. Receptor activity-modifying protein 1 (RAMP1) forms a complex with calcitonin receptor-like receptor to generate the receptor for calcitonin gene-related peptide. The present study examined whether RAMP1 plays a role in increased lymphangiogenesis during secondary lymphedema. METHODS: A model of lymphedema was generated by surgical removal of pre-existing lymphatic vessels from the subcutaneous tissue on the tails of RAMP1-deficient (RAMP1-/-) mice and their wild-type (WT) counterparts. The maximum diameter of the tail, lymphangiogenesis, and macrophage recruitment were then examined. RESULTS: Compared with that in WT mice, lymphedema in the tails in RAMP1-/- mice was sustained, with suppressed lymphangiogenesis and reduced expression of vascular endothelial growth factor-C and vascular endothelial growth factor receptor 3 at the distal edge of the lesions. The newly formed lymphatic vessels in RAMP1-/- mice were dilated, with impaired lymphatic flow. RAMP1 was expressed by macrophages recruited into edematous tail tissues distal to the wound. The number of macrophages in RAMP1-/- mice was higher than that in WT mice. Expression of messenger RNA encoding M1 macrophage-related genes, including tumor necrosis factor-α and interleukin-1, was higher in RAMP1-/- mice than in WT mice, whereas expression of messenger RNA encoding M2 macrophage genes, including interleukin-10, was lower. CONCLUSIONS: RAMP1 signaling improves lymphedema and accelerates lymphangiogenesis associated with reduced recruitment of pro-inflammatory macrophages.
[Mh] Termos MeSH primário: Linfangiogênese/fisiologia
Linfedema/metabolismo
Complicações Pós-Operatórias/metabolismo
Proteína 1 Modificadora da Atividade de Receptores/metabolismo
[Mh] Termos MeSH secundário: Animais
Biomarcadores/metabolismo
Linfedema/etiologia
Linfedema/fisiopatologia
Macrófagos/metabolismo
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Complicações Pós-Operatórias/fisiopatologia
Proteína 1 Modificadora da Atividade de Receptores/deficiência
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Ramp1 protein, mouse); 0 (Receptor Activity-Modifying Protein 1)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171109
[Lr] Data última revisão:
171109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171029
[St] Status:MEDLINE


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[PMID]:28691801
[Au] Autor:Woolley MJ; Simms J; Uddin S; Poyner DR; Conner AC
[Ad] Endereço:College of Medical and Dental Sciences, University of Birmingham , Edgbaston, Birmingham B15 2TT, U.K.
[Ti] Título:Relative Antagonism of Mutants of the CGRP Receptor Extracellular Loop 2 Domain (ECL2) Using a Truncated Competitive Antagonist (CGRP ): Evidence for the Dual Involvement of ECL2 in the Two-Domain Binding Model.
[So] Source:Biochemistry;56(30):3877-3880, 2017 Aug 01.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The second extracellular loop (ECL2) of the G protein-coupled receptor (GPCR) family is important for ligand interaction and drug discovery. ECL2 of the family B cardioprotective calcitonin gene-related peptide (CGRP) receptor is required for cell signaling. Family B GPCR ligands have two regions; the N-terminus mediates receptor activation, and the remainder confers high-affinity binding. Comparing antagonism of CGRP at a number of point mutations of ECL2 of the CGRP receptor, we show that the ECL2 potentially facilitates interaction with up to the 18 N-terminal residues of CGRP. This has implications for understanding family B GPCR activation and for drug design at the CGRP receptor.
[Mh] Termos MeSH primário: Peptídeo Relacionado com Gene de Calcitonina/farmacologia
Proteína Semelhante a Receptor de Calcitonina/agonistas
Mióticos/farmacologia
Modelos Moleculares
Fragmentos de Peptídeos/farmacologia
Proteína 1 Modificadora da Atividade de Receptores/metabolismo
Receptores de Peptídeo Relacionado com o Gene de Calcitonina/agonistas
Transdução de Sinais/efeitos dos fármacos
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Animais
Sítios de Ligação
Ligação Competitiva
Células COS
Peptídeo Relacionado com Gene de Calcitonina/química
Peptídeo Relacionado com Gene de Calcitonina/genética
Peptídeo Relacionado com Gene de Calcitonina/metabolismo
Proteína Semelhante a Receptor de Calcitonina/química
Proteína Semelhante a Receptor de Calcitonina/genética
Proteína Semelhante a Receptor de Calcitonina/metabolismo
Cercopithecus aethiops
Cinética
Ligantes
Mióticos/química
Mióticos/metabolismo
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/genética
Fragmentos de Peptídeos/metabolismo
Mutação Puntual
Conformação Proteica
Domínios e Motivos de Interação entre Proteínas
Mapeamento de Interação de Proteínas
Multimerização Proteica
Proteína 1 Modificadora da Atividade de Receptores/química
Proteína 1 Modificadora da Atividade de Receptores/genética
Receptores de Peptídeo Relacionado com o Gene de Calcitonina/química
Receptores de Peptídeo Relacionado com o Gene de Calcitonina/genética
Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Proteínas Recombinantes/farmacologia
Homologia Estrutural de Proteína
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CALCRL protein, human); 0 (Calcitonin Receptor-Like Protein); 0 (Ligands); 0 (Miotics); 0 (Peptide Fragments); 0 (RAMP1 protein, human); 0 (RCP9 protein, human); 0 (Receptor Activity-Modifying Protein 1); 0 (Receptors, Calcitonin Gene-Related Peptide); 0 (Recombinant Proteins); 119911-68-1 (calcitonin gene-related peptide (8-37)); 83652-28-2 (Calcitonin Gene-Related Peptide)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170811
[Lr] Data última revisão:
170811
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170711
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00077


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[PMID]:28603014
[Au] Autor:Blixt FW; Radziwon-Balicka A; Edvinsson L; Warfvinge K
[Ad] Endereço:Department of Clinical Sciences, Division of Experimental Vascular Research, Lund University, Lund, Sweden.
[Ti] Título:Distribution of CGRP and its receptor components CLR and RAMP1 in the rat retina.
[So] Source:Exp Eye Res;161:124-131, 2017 Aug.
[Is] ISSN:1096-0007
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Calcitonin gene-related peptide (CGRP) is a 37 amino acid neuropeptide with several functions including vasodilation, the perception of painful stimuli, and inflammation. The CGRP receptor consists of two main components; calcitonin-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1). While there is a growing recognition that CGRP plays a key role in migraine, the function of CGRP in the retina has not been fully established. This study aims to investigate the distribution of CGRP and its two receptor components in the rat retina, visually by immunohistochemistry and quantitatively using flow cytometry. CGRP immunoreactivity was found in the Müller cells while CLR/RAMP1 was located in the nerve fiber layer. Furthermore, since almost all RAMP1 immunoreactive cells co-express CLR, we propose that RAMP1 expression in the retina reflects functional CGRP receptors.
[Mh] Termos MeSH primário: Peptídeo Relacionado com Gene de Calcitonina/metabolismo
Proteína Semelhante a Receptor de Calcitonina/metabolismo
Proteína 1 Modificadora da Atividade de Receptores/metabolismo
Retina/metabolismo
[Mh] Termos MeSH secundário: Animais
Biomarcadores/metabolismo
Células Ependimogliais/metabolismo
Citometria de Fluxo
Técnica Indireta de Fluorescência para Anticorpo
Masculino
Fibras Nervosas/metabolismo
Ratos
Ratos Sprague-Dawley
Células Ganglionares da Retina/metabolismo
Distribuição Tecidual
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Calcitonin Receptor-Like Protein); 0 (Calcrl protein, rat); 0 (Ramp1 protein, rat); 0 (Receptor Activity-Modifying Protein 1); 83652-28-2 (Calcitonin Gene-Related Peptide)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170821
[Lr] Data última revisão:
170821
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170613
[St] Status:MEDLINE


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[PMID]:28552562
[Au] Autor:Yuan J; Gilbert ER; Cline MA
[Ad] Endereço:National Engineering Laboratory for Animal Breeding and MOA Key Laboratory of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, People's Republic of China; Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, United States.
[Ti] Título:The central anorexigenic mechanism of amylin in Japanese quail (Coturnix japonica) involves pro-opiomelanocortin, calcitonin receptor, and the arcuate nucleus of the hypothalamus.
[So] Source:Comp Biochem Physiol A Mol Integr Physiol;210:28-34, 2017 Aug.
[Is] ISSN:1531-4332
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Amylin is a 37-amino acid peptide hormone that exerts anorexigenic effects in humans and animals. We demonstrated that central injection of amylin into chicks affected feeding and related behaviors via the hypothalamus and brainstem, although the molecular mechanisms remained elusive. Thus, the objective of this study was to investigate the molecular mechanisms underlying anorexigenic effects of amylin in 7 day-old Japanese quail. Food but not water intake was reduced after intracerebroventricular amylin injection, and the behavior analysis indicated that this was associated with decreased food pecks and preening. Whole hypothalamus and hypothalamic nuclei including the arcuate nucleus (ARC), paraventricular nucleus (PVN), ventromedial hypothalamus (VMH), dorsomedial nucleus (DMN) and lateral hypothalamic area (LH) were extracted from quail at 1h post-injection for total RNA isolation. Real time PCR was performed to quantify mRNA abundance of amylin receptors, appetite-associated neuropeptides and monoamine-synthesis-related enzymes. Central amylin injection increased the mRNA abundance of calcitonin receptor (CALCR), receptor activity modifying protein 1 (RAMP1), pro-opiomelanocortin (POMC), and aromatic l-amino acid decarboxylase (AADC) in the hypothalamus and individual hypothalamic nuclei. Relative quantities of CALCR and POMC mRNA were greater in the ARC of the amylin- than vehicle-treated group. Thus, amylin-mediated effects on food intake may involve POMC, monoamine synthesis, and amylin receptor 1 (a complex of CALCR and RAMP1) in the ARC. Together, these data provide novel insights on the hypothalamic-specific molecular mechanisms of amylin-induced food intake.
[Mh] Termos MeSH primário: Coturnix/fisiologia
Ingestão de Alimentos
Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo
Pró-Opiomelanocortina/metabolismo
Receptores da Calcitonina/metabolismo
[Mh] Termos MeSH secundário: Animais
Apetite/fisiologia
Núcleo Arqueado do Hipotálamo/efeitos dos fármacos
Núcleo Arqueado do Hipotálamo/metabolismo
Núcleo Arqueado do Hipotálamo/fisiologia
Descarboxilases de Aminoácido-L-Aromático/genética
Descarboxilases de Aminoácido-L-Aromático/metabolismo
Ingestão de Líquidos
Ingestão de Alimentos/efeitos dos fármacos
Regulação da Expressão Gênica/efeitos dos fármacos
Hipotálamo/efeitos dos fármacos
Hipotálamo/fisiologia
Polipeptídeo Amiloide das Ilhotas Pancreáticas/farmacologia
Pró-Opiomelanocortina/genética
Proteína 1 Modificadora da Atividade de Receptores/genética
Proteína 1 Modificadora da Atividade de Receptores/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Islet Amyloid Polypeptide); 0 (Receptor Activity-Modifying Protein 1); 0 (Receptors, Calcitonin); 66796-54-1 (Pro-Opiomelanocortin); EC 4.1.1.28 (Aromatic-L-Amino-Acid Decarboxylases)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170724
[Lr] Data última revisão:
170724
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170530
[St] Status:MEDLINE


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[PMID]:28192258
[Au] Autor:Sheykhzade M; Amandi N; Pla MV; Abdolalizadeh B; Sams A; Warfvinge K; Edvinsson L; Pickering DS
[Ad] Endereço:Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Electronic address: mash@sund.ku.dk.
[Ti] Título:Binding and functional pharmacological characteristics of gepant-type antagonists in rat brain and mesenteric arteries.
[So] Source:Vascul Pharmacol;90:36-43, 2017 Mar.
[Is] ISSN:1879-3649
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:AIM: The neuropeptide calcitonin gene-related peptide (CGRP) is found in afferent sensory nerve fibers innervating the resistance arteries and plays a pivotal role in a number of neurovascular diseases such as migraine and subarachnoid bleedings. The present study investigates the binding and antagonistic characteristics of small non-peptide CGRP receptor antagonists (i.e. gepants) in isolated rat brain and mesenteric resistance arteries. METHODS: The antagonistic behavior of gepants was investigated in isolated rat mesenteric arteries using a wire myograph setup while binding of gepants to CGRP receptors was investigated in rat brain membranes using a radioligand competitive binding assay. Furthermore, the histological location of the key components of CGRP receptor (RAMP1 and CLR) was assessed by immunohistochemistry. RESULTS: Our functional studies clearly show that all gepants are reversible competitive antagonists producing Schild plot slopes not significantly different from unity and thus suggesting presence of a uniform CGRP receptor population in the arteries. A uniform receptor population was also confirmed by radioligand competitive binding studies showing similar affinities for the gepants in rat brain and mesenteric arteries, the exception being rimegepant which had 50-fold lower affinity in brain than mesenteric arteries. CLR and RAMP1 were shown to be located in both vascular smooth muscle and endothelial cells of rat mesenteric arteries by immunohistochemistry. CONCLUSION: The present results indicate that, despite species differences in the CGRP receptor affinity, the antagonistic nature of these gepants, the distribution pattern of CGRP receptor components and the mechanism behind CGRP-induced vasodilation seem to be similar in resistance-sized arteries of human and rats.
[Mh] Termos MeSH primário: Azepinas/farmacologia
Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia
Cerebelo/irrigação sanguínea
Artérias Cerebrais/efeitos dos fármacos
Dipeptídeos/farmacologia
Imidazóis/farmacologia
Artérias Mesentéricas/efeitos dos fármacos
Piperidinas/farmacologia
Piridinas/farmacologia
Quinazolinas/farmacologia
Receptores de Peptídeo Relacionado com o Gene de Calcitonina/antagonistas & inibidores
Compostos de Espiro/farmacologia
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Animais
Ligação Competitiva
Peptídeo Relacionado com Gene de Calcitonina/metabolismo
Peptídeo Relacionado com Gene de Calcitonina/farmacologia
Proteína Semelhante a Receptor de Calcitonina/metabolismo
Artérias Cerebrais/metabolismo
Relação Dose-Resposta a Droga
Células Endoteliais/efeitos dos fármacos
Células Endoteliais/metabolismo
Feminino
Seres Humanos
Técnicas In Vitro
Ligantes
Masculino
Artérias Mesentéricas/metabolismo
Músculo Liso Vascular/efeitos dos fármacos
Músculo Liso Vascular/metabolismo
Miografia
Ligação Proteica
Ensaio Radioligante
Ratos Sprague-Dawley
Proteína 1 Modificadora da Atividade de Receptores/metabolismo
Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo
Sus scrofa
Vasodilatação/efeitos dos fármacos
Vasodilatadores/metabolismo
Vasodilatadores/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 ((5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta(b)pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo(4,5-b)pyridin-1-yl)piperidine-1-carboxylate); 0 (2-(8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro(4.5)dec-9-yl)-N-(2'-oxo-1,1',2',3-tetrahydrospiro(indene-2,3'-pyrrolo(2,3-b)pyridin)-5-yl)acetamide); 0 (Azepines); 0 (Bridged Bicyclo Compounds, Heterocyclic); 0 (Calcitonin Receptor-Like Protein); 0 (Calcrl protein, rat); 0 (Dipeptides); 0 (Imidazoles); 0 (Ligands); 0 (Piperidines); 0 (Pyridines); 0 (Quinazolines); 0 (Ramp1 protein, rat); 0 (Receptor Activity-Modifying Protein 1); 0 (Receptors, Calcitonin Gene-Related Peptide); 0 (Spiro Compounds); 0 (Vasodilator Agents); 83652-28-2 (Calcitonin Gene-Related Peptide); D42O649ALL (telcagepant); WOA5J8TX6M (olcegepant)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170724
[Lr] Data última revisão:
170724
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170214
[St] Status:MEDLINE


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[PMID]:28053042
[Au] Autor:Mason BN; Kaiser EA; Kuburas A; Loomis MM; Latham JA; Garcia-Martinez LF; Russo AF
[Ad] Endereço:Molecular and Cellular Biology Program.
[Ti] Título:Induction of Migraine-Like Photophobic Behavior in Mice by Both Peripheral and Central CGRP Mechanisms.
[So] Source:J Neurosci;37(1):204-216, 2017 Jan 04.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The neuropeptide calcitonin gene-related peptide (CGRP) is a key player in migraine. Although migraine can be treated using CGRP antagonists that act peripherally, the relevant sites of CGRP action remain unknown. To address the role of CGRP both within and outside the CNS, we used CGRP-induced light-aversive behavior in mice as a measure of migraine-associated photophobia. Peripheral (intraperitoneal) injection of CGRP resulted in light-aversive behavior in wild-type CD1 mice similar to aversion seen previously after central (intracerebroventricular) injection. The phenotype was also observed in C57BL/6J mice, although to a lesser degree and with more variability. After intraperitoneal CGRP, motility was decreased in the dark only, similar to motility changes after intracerebroventricular CGRP. In addition, as with intracerebroventricular CGRP, there was no general increase in anxiety as measured in an open-field assay after intraperitoneal CGRP. Importantly, two clinically effective migraine drugs, the 5-HT agonist sumatriptan and a CGRP-blocking monoclonal antibody, attenuated the peripheral CGRP-induced light aversion and motility behaviors. To begin to address the mechanism of peripheral CGRP action, we used transgenic CGRP-sensitized mice that have elevated levels of the CGRP receptor hRAMP1 subunit in nervous tissue (nestin/hRAMP1). Surprisingly, sensitivity to low light was not seen after intraperitoneal CGRP injection, but was seen after intracerebroventricular CGRP injection. These results suggest that CGRP can act in both the periphery and the brain by distinct mechanisms and that CGRP actions may be transmitted to the CNS via indirect sensitization of peripheral nerves. SIGNIFICANCE STATEMENT: The neuropeptide calcitonin gene-related peptide (CGRP) is a central player in migraine pathogenesis, yet its site(s) of action remains unknown. Some preclinical studies have pointed to central sites in the brain and brainstem. However, a peripheral site of action is indicated by the ability of intravenous CGRP to trigger migraine in humans and the efficacy of CGRP receptor antagonists that evidently do no penetrate the CNS in effective amounts. Resolving this issue is particularly important given recent clinical trials showing that anti-CGRP monoclonal antibodies can reduce and even prevent migraine attacks. In this study, we report that CGRP can act in both the brain and the periphery of the mouse to cause migraine-like photophobia by apparently distinct mechanisms.
[Mh] Termos MeSH primário: Peptídeo Relacionado com Gene de Calcitonina/farmacologia
Transtornos de Enxaqueca/psicologia
Fotofobia/psicologia
[Mh] Termos MeSH secundário: Animais
Ansiedade/psicologia
Peptídeo Relacionado com Gene de Calcitonina/administração & dosagem
Peptídeo Relacionado com Gene de Calcitonina/antagonistas & inibidores
Escuridão
Feminino
Injeções Intraperitoneais
Luz
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Atividade Motora
Nestina/genética
Proteína 1 Modificadora da Atividade de Receptores/genética
Agonistas de Receptores de Serotonina/farmacologia
Sumatriptana/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nestin); 0 (Ramp1 protein, mouse); 0 (Receptor Activity-Modifying Protein 1); 0 (Serotonin Receptor Agonists); 83652-28-2 (Calcitonin Gene-Related Peptide); 8R78F6L9VO (Sumatriptan)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170106
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.2967-16.2016


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[PMID]:27662515
[Au] Autor:Dyukova E; Schreckenberg R; Arens C; Sitdikova G; Schlüter KD
[Ad] Endereço:Physiologisches Institut, Justus-Liebig-Universität Gießen, Giessen, Germany.
[Ti] Título:The Role of Calcium-Sensing Receptors in Endothelin-1-Dependent Effects on Adult Rat Ventricular Cardiomyocytes: Possible Contribution to Adaptive Myocardial Hypertrophy.
[So] Source:J Cell Physiol;232(9):2508-2518, 2017 Sep.
[Is] ISSN:1097-4652
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Nitric oxide (NO)-deficiency as it occurs during endothelial dysfunction activates the endothelin-1 (ET-1) system and increases the expression of receptor activity modifying protein (RAMP)-1 that acts as a chaperon for calcium-sensing receptors (CaR) that have recently been identified to improve cardiac function. Here, we hypothesized that ET-1 increases the cardiac expression of CaR and thereby induces an adaptive type of hypertrophy. Expressions of RAMP-1, endothelin receptors, and CaR were analyzed by RT-PCR in left ventricular tissues of L-NAME-treated rats. Effects of ET-1 on CaR expression and cell function (load free cell shortening) were analyzed in adult rat ventricular cardiomyocytes. siRNA directed against CaR and RAMP-1 was used to investigate a causal relationship. PD142893 and BQ788 were used to dissect the contribution of ET , ET , and ET receptors. Non-specific NO synthase inhibition with L-Nitro arginine methyl ester (L-NAME) caused a cardiac upregulation of ET receptors and CaR suggesting a paracrine effect of ET-1 on cardiomyocytes. Indeed, ET-1 induced the expression of CaR in cultured cardiomyocytes. Under these conditions, cardiomyocytes increased cell size (hypertrophy) but maintained normal function. Inhibition of ET and ET receptors led to ET-1-dependent reduction in cell shortening and attenuated up-regulation of CaR. Down-regulation of RAMP-1 reduced CaR responsiveness. In conclusion, ET-1 causes an adaptive type of hypertrophy by up-regulation of CaR in cardiomyocytes via ET and/or ET receptors. J. Cell. Physiol. 232: 2508-2518, 2017. © 2016 Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: Cardiomegalia/metabolismo
Endotelina-1/farmacologia
Ventrículos do Coração/efeitos dos fármacos
Miócitos Cardíacos/efeitos dos fármacos
Receptores de Detecção de Cálcio/efeitos dos fármacos
Função Ventricular Esquerda/efeitos dos fármacos
Remodelação Ventricular/efeitos dos fármacos
[Mh] Termos MeSH secundário: Adaptação Fisiológica
Animais
Cardiomegalia/genética
Cardiomegalia/patologia
Cardiomegalia/fisiopatologia
Células Cultivadas
Modelos Animais de Doenças
Ventrículos do Coração/metabolismo
Ventrículos do Coração/patologia
Ventrículos do Coração/fisiopatologia
Preparação de Coração Isolado
Miócitos Cardíacos/metabolismo
Miócitos Cardíacos/patologia
Óxido Nítrico/metabolismo
Óxido Nítrico Sintase/metabolismo
Comunicação Parácrina
Interferência de RNA
Ratos Wistar
Proteína 1 Modificadora da Atividade de Receptores/metabolismo
Receptor de Endotelina A/agonistas
Receptor de Endotelina A/genética
Receptor de Endotelina A/metabolismo
Receptor de Endotelina B/agonistas
Receptor de Endotelina B/genética
Receptor de Endotelina B/metabolismo
Receptores de Detecção de Cálcio/genética
Receptores de Detecção de Cálcio/metabolismo
Transdução de Sinais/efeitos dos fármacos
Transfecção
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Endothelin-1); 0 (Ramp1 protein, rat); 0 (Receptor Activity-Modifying Protein 1); 0 (Receptor, Endothelin A); 0 (Receptor, Endothelin B); 0 (Receptors, Calcium-Sensing); 0 (extracellular calcium cation-sensing receptor, rat); 31C4KY9ESH (Nitric Oxide); EC 1.14.13.39 (Nitric Oxide Synthase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170808
[Lr] Data última revisão:
170808
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160924
[St] Status:MEDLINE
[do] DOI:10.1002/jcp.25612


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[PMID]:27554772
[Au] Autor:Ringer C; Tune S; Bertoune MA; Schwarzbach H; Tsujikawa K; Weihe E; Schütz B
[Ad] Endereço:Department of Molecular Neurosciences, Institute of Anatomy and Cell Biology, Philipps-University, Robert-Koch-Strasse 8, 35037, Marburg, Germany.
[Ti] Título:Disruption of calcitonin gene-related peptide signaling accelerates muscle denervation and dampens cytotoxic neuroinflammation in SOD1 mutant mice.
[So] Source:Cell Mol Life Sci;74(2):339-358, 2017 Jan.
[Is] ISSN:1420-9071
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease. Neuronal vacuolization and glial activation are pathologic hallmarks in the superoxide dismutase 1 (SOD1) mouse model of ALS. Previously, we found the neuropeptide calcitonin gene-related peptide (CGRP) associated with vacuolization and astrogliosis in the spinal cord of these mice. We now show that CGRP abundance positively correlated with the severity of astrogliosis, but not vacuolization, in several motor and non-motor areas throughout the brain. SOD1 mice harboring a genetic depletion of the ßCGRP isoform showed reduced CGRP immunoreactivity associated with vacuolization, while motor functions, body weight, survival, and astrogliosis were not altered. When CGRP signaling was completely disrupted through genetic depletion of the CGRP receptor component, receptor activity-modifying protein 1 (RAMP1), hind limb muscle denervation, and loss of muscle performance were accelerated, while body weight and survival were not affected. Dampened neuroinflammation, i.e., reduced levels of astrogliosis in the brain stem already in the pre-symptomatic disease stage, and reduced microgliosis and lymphocyte infiltrations during the late disease phase were additional neuropathology features in these mice. On the molecular level, mRNA expression levels of brain-derived neurotrophic factor (BDNF) and those of the anti-inflammatory cytokine interleukin 6 (IL-6) were elevated, while those of several pro-inflammatory cytokines found reduced in the brain stem of RAMP1-deficient SOD1 mice at disease end stage. Our results thus identify an important, possibly dual role of CGRP in ALS pathogenesis.
[Mh] Termos MeSH primário: Encéfalo/patologia
Peptídeo Relacionado com Gene de Calcitonina/metabolismo
Inflamação/metabolismo
Inflamação/patologia
Denervação Muscular
Transdução de Sinais
Superóxido Dismutase-1/genética
[Mh] Termos MeSH secundário: Animais
Astrócitos/metabolismo
Astrócitos/patologia
Encéfalo/metabolismo
Morte Celular
Quimiocinas/metabolismo
Progressão da Doença
Regulação da Expressão Gênica
Seres Humanos
Hibridização Genética
Linfócitos/patologia
Camundongos Mutantes
Camundongos Transgênicos
Modelos Biológicos
Neurônios Motores/metabolismo
Neurônios Motores/patologia
Fatores de Crescimento Neural/metabolismo
Proteína 1 Modificadora da Atividade de Receptores/deficiência
Proteína 1 Modificadora da Atividade de Receptores/metabolismo
Superóxido Dismutase-1/metabolismo
Vacúolos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Chemokines); 0 (Nerve Growth Factors); 0 (Ramp1 protein, mouse); 0 (Receptor Activity-Modifying Protein 1); 83652-28-2 (Calcitonin Gene-Related Peptide); EC 1.15.1.1 (Superoxide Dismutase-1)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170912
[Lr] Data última revisão:
170912
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160825
[St] Status:MEDLINE
[do] DOI:10.1007/s00018-016-2337-4


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[PMID]:27513455
[Au] Autor:Kawashima-Takeda N; Ito Y; Nishizawa N; Kawashima R; Tanaka K; Tsujikawa K; Watanabe M; Majima M
[Ad] Endereço:Department of Surgery, Kitasato University School of Medicine, Sagamihara, Japan.
[Ti] Título:RAMP1 suppresses mucosal injury from dextran sodium sulfate-induced colitis in mice.
[So] Source:J Gastroenterol Hepatol;32(4):809-818, 2017 Apr.
[Is] ISSN:1440-1746
[Cp] País de publicação:Australia
[La] Idioma:eng
[Ab] Resumo:BACKGROUND AND AIMS: Calcitonin gene-related peptide (CGRP) is thought to be involved in the modulation of intestinal motility. CGRP receptor is composed of receptor activity-modifying protein (RAMP) 1 combined with calcitonin receptor-like receptor (CRLR) for CGRP. The study investigated the role of CGRP in mice with experimentally induced colitis. METHODS: The study used dextran sodium sulfate (DSS) to induce colitis in mice. The study compared the severity of colitis in wild-type (WT) mice, mice treated with a CGRP receptor antagonist (CGRP ), and RAMP1 knockout ( ) mice. Pathological changes in the mucosa were assessed, and inflammatory cells and cytokine levels were measured. RESULTS: The severity of inflammation in DSS-induced colitis increased markedly in CGRP -treated mice and RAMP1 mice compared with WT mice. RAMP1 mice showed more severe damage compared with CGRP -treated mice. The number of periodic acid-Schiff-positive cells decreased in CGRP -treated mice compared with WT mice and was even further decreased in RAMP1 mice. RAMP1 was expressed by macrophages, mast cells, and T-cells. RAMP1 mice exhibited excessive accumulation of macrophages and mast cells into the colonic tissue with increased levels of tumor necrosis factor-α and interleukin-1ß as compared with WT mice. Infiltration of T-cells into the colonic mucosa, which was associated with the expression of T helper (Th) cytokines including Th1 (interferon gamma) and Th17 (IL-17), was augmented in RAMP1 mice. CONCLUSIONS: The findings of this study suggest that RAMP1 exerted mucosal protection in DSS-induced colitis via attenuation of recruitment of inflammatory cells and of pro-inflammatory cytokines.
[Mh] Termos MeSH primário: Colite/induzido quimicamente
Colite/genética
Sulfato de Dextrana/efeitos adversos
Mucosa Intestinal/efeitos dos fármacos
Mucosa Intestinal/patologia
Proteína 1 Modificadora da Atividade de Receptores/fisiologia
[Mh] Termos MeSH secundário: Animais
Peptídeo Relacionado com Gene de Calcitonina/fisiologia
Colite/patologia
Citocinas/metabolismo
Mediadores da Inflamação/metabolismo
Interleucina-1beta/metabolismo
Mucosa Intestinal/metabolismo
Masculino
Camundongos Endogâmicos C57BL
Camundongos Knockout
Proteína 1 Modificadora da Atividade de Receptores/metabolismo
Índice de Gravidade de Doença
Linfócitos T/patologia
Fator de Necrose Tumoral alfa/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytokines); 0 (Inflammation Mediators); 0 (Interleukin-1beta); 0 (Ramp1 protein, mouse); 0 (Receptor Activity-Modifying Protein 1); 0 (Tumor Necrosis Factor-alpha); 83652-28-2 (Calcitonin Gene-Related Peptide); 9042-14-2 (Dextran Sulfate)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160812
[St] Status:MEDLINE
[do] DOI:10.1111/jgh.13505



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