Functional consequences of CCR7 Study of CCR2/CCR7, CCR5/CCR7 and CXCR4/CCR7 heteromers
Ficheiros
Data
2010
Autores
Título da revista
ISSN da revista
Título do Volume
Editora
Resumo
Os receptores das quimiocinas constituem uma grande família de receptores da superfície celular responsáveis por importantes funções biológicas. Tradicionalmente, tal como os restantes GPCRs, os receptores das quimiocinas têm sido considerados entidades monoméricas, no entanto, esta concepção tem vindo a modificar-se nos últimos anos com a acumulação de evidências indicando que estes receptores podem formar dímeros. Este novo conceito de dimerização deve ser considerado uma vez que poderá conferir novas propriedades funcionais e consequentemente novos perfis farmacológicos a este receptores que constituem importantes alvos farmacológicos devido ao seu papel em diversos processos patológicos. Assim, este trabalho teve como objectivo investigar as consequências funcionais da heterodimerização do receptor CCR7 com os receptores CCR2, CCR5 ou CXCR4.
Verificou-se em células CHO, que quando o receptor CCR7 é coexpresso com os receptores CCR5 ou CXCR4 a activação destes dois receptores é diminuída sem que se verifique a sua internalização, pelo contrário a activação do receptor CCR2 é aumentada quando coexpresso com o receptor CCR7, sendo CCR2 internalizado. Foi ainda testado em células H9 e Jurkat se a alteração da expressão do receptor CCR7 poderia afectar a funcionalidade do receptor CXCR4. A diminuição da expressão do receptor CCR7 em células H9, pela transfecção de RNAi, conduz a uma diminuição da expressão do receptor CXCR4 da superfície celular bem como a uma diminuição na activação deste receptor. Finalmente, não foram observadas diferenças significativas na activação do receptor CXCR4 entre células Jurkat que expressam CCR7 e células Jurkat que não expressam CCR7.
Chemokine receptors are a large family of cell surface receptors responsible for a number of biological functions. Like others G-protein coupled receptors (GPCRs), chemokine receptors (CCR) traditionally have been thought to act as monomers, but in the past few years a number of evidences suggesting that chemokine receptors may form dimers have been accumulated. The role of these receptors in several pathological processes makes them an interesting target to therapeutic drugs development and this concept of dimerization can be essential in the functional properties and consequently in the pharmacological profile of these receptors. In this study, we investigated the functional consequences of CCR7 heterodimerization with CCR2, CCR5 and/or CXCR4. We show, in CHO cells, that when CCR5 or CXCR4 are coexpressed with CCR7 their function is decreased; however the presence of CCR7 does not affect the internalization of these receptors. Contrary, when CCR2 is co-expressed with CCR7, CCR2 function is increased but this receptor is not internalized. We also tested in Jurkat and H9 cells whether the alteration of CCR7 expression could modify the CXCR4 function. Transfection of H9 cells with RNAi targeting to CCR7 leads a decrease in the expression of this receptor at the cell surface as well as the CXCR4 expression being the functionality these receptors decreased according to the expression at cell surface. Finally, we failed to see any significant differences on CXCR4 function in Jurkat cells expressing CCR7and Jurkat cells that do not express CCR7.
Chemokine receptors are a large family of cell surface receptors responsible for a number of biological functions. Like others G-protein coupled receptors (GPCRs), chemokine receptors (CCR) traditionally have been thought to act as monomers, but in the past few years a number of evidences suggesting that chemokine receptors may form dimers have been accumulated. The role of these receptors in several pathological processes makes them an interesting target to therapeutic drugs development and this concept of dimerization can be essential in the functional properties and consequently in the pharmacological profile of these receptors. In this study, we investigated the functional consequences of CCR7 heterodimerization with CCR2, CCR5 and/or CXCR4. We show, in CHO cells, that when CCR5 or CXCR4 are coexpressed with CCR7 their function is decreased; however the presence of CCR7 does not affect the internalization of these receptors. Contrary, when CCR2 is co-expressed with CCR7, CCR2 function is increased but this receptor is not internalized. We also tested in Jurkat and H9 cells whether the alteration of CCR7 expression could modify the CXCR4 function. Transfection of H9 cells with RNAi targeting to CCR7 leads a decrease in the expression of this receptor at the cell surface as well as the CXCR4 expression being the functionality these receptors decreased according to the expression at cell surface. Finally, we failed to see any significant differences on CXCR4 function in Jurkat cells expressing CCR7and Jurkat cells that do not express CCR7.
Descrição
Dissertação de Mestrado em Biotecnologia para as Ciências da Saúde
Palavras-chave
Recetores de quimiocinas , GCPRs