Les hétérodimères des récepteurs AT1 de l'angiotensine II et des récepteurs alpha 2 adrénergiques de sous-types A et C

En France, l'hypertension est la première cause de mortalité et se caractérise par une hyperactivité du Système Nerveux Sympathique (SNS) et du Système Rénine-Angiotensine (SRA). L'hyperactivité du SNS entraîne une hyperactivité du SRA qui via l'hypersécrétion d'angiotensine II (AngII) induit l'hypersécrétion de Noradrénaline (NA). Au niveau de la terminaison nerveuse sympathique, la stimulation par l'AngII des récepteurs AT1 (AT1R) de l'AngII améliore la libération de NA. Cependant, les mécanismes moléculaires restent à ce jour mal établis. En utilisant le principe du transfert d'énergie bioluminescente par résonnance (BRET), nous avons démontré l'existence d'hétérodimères constitutifs entre les Récepteurs Couplés aux Protéines G AT1R et a2-adrénergiques A et C (a2A/CR), l'induction de changements conformationnels par des ligands agonistes (AngII, NE) et antagonistes (losartan, irbésartan) définis par les modulations du signal BRET, et le couplage sélectif d'AT1R avec la protéine Ga11.TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Ephrine-B1 (une nouvelle protéine structurante des membranes latérales des cardiomyocytes adultes)

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Caractérisation des dimères de récepteurs à l'angiotensine II AT1 et a2C-adrénergiques et conséquences fonctionnelles

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

BIASED SIGNALING AT CHEMOKINE RECEPTORS

info:eu-repo/semantics/nonPublishe

Partial agonist and biased signalling properties of the synthetic enantiomers J113863/UCB35625 at chemokine receptors CCR2 and CCR5

Biased agonism at G protein-coupled receptors constitutes a promising area of research for the identification of new therapeutic molecules. In this study we identified two novel biased ligands for the chemokine receptors CCR2 and CCR5 and characterized their functional properties. We showed that J113863 and its enantiomer UCB35625, initially identified as high affinity antagonists for CCR1 and CCR3, also bind with low affinity to the closely related receptors CCR2 and CCR5. Binding of J113863 and UCB35625 to CCR2 or CCR5 resulted in the full or partial activation of the three Gi proteins and the two Go isoforms. Unlike chemokines, the compounds did not activate G12. Binding of J113863 to CCR2 or CCR5 also induced the recruitment of -arrestin 2, whereas UCB35625 did not. UCB35625 induced the chemotaxis of L1.2 cells expressing CCR2 or CCR5. In contrast, J113863 induced the migration of L1.2-CCR2 cells but antagonized the chemokine-induced migration of L1.2- CCR5 cells. We also showed that replacing the phenylalanine 3.33 in CCR5 TM3 by the corresponding histidine of CCR2 converts J113863 from an antagonist for cell migration and a partial agonist in other assays to a full agonist in all assays. Further analyses indicated that F3.33H substitution strongly increased the activation of G proteins and β-arrestin 2 by J113863. These results highlight the biased nature of the J113863 and UCB35625 that act either as antagonist, partial agonist, or full agonist according to the receptor, the enantiomer, and the signaling pathway investigated.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Study of biased signaling at chemokine receptors

info:eu-repo/semantics/nonPublishe

Synthetic enantiomers and biased signaling at chemokine receptors

info:eu-repo/semantics/nonPublishe

Upregulation of chemokine receptor CCR7 during B cell development controls CXCR4 responsiveness and bone marrow homing

info:eu-repo/semantics/nonPublishe

Chemokine receptor CCR7 controls CXCR4 responsiveness during B cells development

info:eu-repo/semantics/nonPublishe

Coexpression of CCR7 and CXCR4 During B Cell Development Controls CXCR4 Responsiveness and Bone Marrow Homing.

The CXCL12-CXCR4 axis plays a key role in the retention of stem cells and progenitors in dedicated bone marrow niches. It is well-known that CXCR4 responsiveness in B lymphocytes decreases dramatically during the final stages of their development in the bone marrow. However, the molecular mechanism underlying this regulation and whether it plays a role in B-cell homeostasis remain unknown. In the present study, we show that the differentiation of pre-B cells into immature and mature B cells is accompanied by modifications to the relative expression of chemokine receptors, with a two-fold downregulation of CXCR4 and upregulation of CCR7. We demonstrate that expression of CCR7 in B cells is involved in the selective inactivation of CXCR4, and that mature B cells from CCR7-/- mice display higher responsiveness to CXCL12 and improved retention in the bone marrow. We also provide molecular evidence supporting a model in which upregulation of CCR7 favors the formation of CXCR4-CCR7 heteromers, wherein CXCR4 is selectively impaired in its ability to activate certain G-protein complexes. Collectively, our results demonstrate that CCR7 behaves as a novel selective endogenous allosteric modulator of CXCR4.info:eu-repo/semantics/publishe