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1.
Commun Biol ; 4(1): 776, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34163006

RESUMO

Agonist bias occurs when different ligands produce distinct signalling outputs when acting at the same receptor. However, its physiological relevance is not always clear. Using primary human cells and gene editing techniques, we demonstrate endogenous agonist bias with physiological consequences for the calcitonin receptor-like receptor, CLR. By switching the receptor-activity modifying protein (RAMP) associated with CLR we can "re-route" the physiological pathways activated by endogenous agonists calcitonin gene-related peptide (CGRP), adrenomedullin (AM) and adrenomedullin 2 (AM2). AM2 promotes calcium-mediated nitric oxide signalling whereas CGRP and AM show pro-proliferative effects in cardiovascular cells, thus providing a rationale for the expression of the three peptides. CLR-based agonist bias occurs naturally in human cells and has a fundamental purpose for its existence. We anticipate this will be a starting point for more studies into RAMP function in native environments and their importance in endogenous GPCR signalling.


Assuntos
Adrenomedulina/fisiologia , Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Hormônios Peptídicos/fisiologia , Receptores Acoplados a Proteínas G/agonistas , Proteína Semelhante a Receptor de Calcitonina/fisiologia , Células Cultivadas , AMP Cíclico/metabolismo , Células Endoteliais/fisiologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Receptores de Adrenomedulina/agonistas , Receptores de Adrenomedulina/análise , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/fisiologia
2.
Brain Res ; 1644: 183-91, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27184601

RESUMO

Adrenomedullin (AM), a member of the calcitonin gene-related peptide (CGRP) family, has been demonstrated to be a pain peptide. This study investigated the possible involvement of AM in tumor necrosis factor-alpha (TNF-α)-induced responses contributing to neuronal plasticity in the dorsal root ganglia (DRG). Exposure of the DRG explant cultures to TNF-α (5nM) for 48h upregulated the expression of AM mRNA. The treatment with TNF-α also increased the level of CGRP, CCL-2 and MMP-9 mRNA in the cultured DRG. This increase was attenuated by the co-treatment with the selective AM receptor antagonist AM22-52 (2µM). The blockade of AM receptors inhibited TNF-α-induced increase of the glial fibrillary acidic protein (GFAP), interleukin-1ß (IL-1ß), phosphorylated cAMP response element binding protein (pCREB) and nuclear factor kappa B (pNF-κB) proteins. On the other hand, the treatment with the AM receptor agonist AM1-50 (10nM) for 96h induced an increase in the level of GFAP, IL-1ß, pCREB and pNF-κB proteins. The inhibition of AM activity did not change TNF-α-induced phosphorylation of extracellular signal-related kinase (pERK) while the treatment with AM1-50 still increased the level of pERK in the cultured DRG. Immunofluorescence assay showed the colocalization of AM-like immunoreactivity (IR) with TNF-α-IR in DRG neurons. The present study suggests that the increased AM receptor signaling mediated the many, but not all, TNF-α-induced activities, contributing to peripheral sensitization in neuropathic pain.


Assuntos
Adrenomedulina/metabolismo , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Receptores de Adrenomedulina/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Adrenomedulina/farmacologia , Animais , Técnicas de Cultura de Células , Quimiocina CCL2/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Interleucina-1beta/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fragmentos de Peptídeos/farmacologia , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Adrenomedulina/agonistas , Receptores de Adrenomedulina/antagonistas & inibidores
3.
Biol Reprod ; 91(3): 65, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25061099

RESUMO

Accumulating data suggest that adrenomedullin (ADM) regulates the trophoblast cell growth, migration, and invasion. However, the effect of ADM on trophoblast differentiation is poorly understood. In this study, we hypothesized that ADM promotes the differentiation of trophoblast stem cells (TSCs) into trophoblast giant cells (TGCs). Using rat TSCs, Rcho-1 cells, we investigated the effect of ADM on TSC differentiation into TGCs in differentiation or stem cell media, respectively, and explored the effect of ADM on the mechanistic target of rapamycin (MTOR) signaling in trophoblast cell differentiation. The results include: 1) in the presence of differentiation medium, 10⁻7 M ADM, but not lower doses, elevated (P < 0.05) Prl3b1/Esrrb (i.e., the ratio of mRNA levels) by 1.7-fold compared to that in control; 2) the supplementation of ADM antagonist, regardless of the concentration of ADM, reduced (P < 0.05) Prl3b1/Esrrb by 2-fold, compared to control group, while the supplementation of CGRP antagonist, regardless of the concentration of ADM, did not change Prl3b1/Esrrb; 3) in the presence of stem cell medium, ADM did not alter the expression of TSC and TGC marker genes, however, the ratio of Prl3b1/Esrrb was reduced (P < 0.05) by ADM antagonist compared to that in control; and 4) ADM increased (P < 0.05) phosphorylated MTOR proteins and the ratio of phosphorylated to total MTOR proteins by 2.0- and 1.7-fold, respectively. The results indicate that ADM promotes but does not induce the differentiation of TSCs to TGCs in a dose-dependent manner and MTOR signaling may play a role in this process.


Assuntos
Adrenomedulina/metabolismo , Proteína Semelhante a Receptor de Calcitonina/agonistas , Proteína 2 Modificadora da Atividade de Receptores/agonistas , Receptores de Adrenomedulina/agonistas , Transdução de Sinais , Células-Tronco/metabolismo , Trofoblastos/metabolismo , Adrenomedulina/antagonistas & inibidores , Adrenomedulina/farmacologia , Animais , Antígenos de Diferenciação/metabolismo , Biomarcadores/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Proteína Semelhante a Receptor de Calcitonina/antagonistas & inibidores , Proteína Semelhante a Receptor de Calcitonina/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Tamanho Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Fosforilação/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Ratos , Proteína 2 Modificadora da Atividade de Receptores/metabolismo , Receptores de Adrenomedulina/antagonistas & inibidores , Receptores de Adrenomedulina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Serina-Treonina Quinases TOR/química , Serina-Treonina Quinases TOR/metabolismo , Trofoblastos/citologia , Trofoblastos/efeitos dos fármacos
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