Probing biased/partial agonism at the G protein-coupled A(2B) adenosine receptor.
Biochem Pharmacol
; 90(3): 297-306, 2014 Aug 01.
Article
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| MEDLINE
| ID: mdl-24853985
ABSTRACT
G protein-coupled A(2B) adenosine receptor (AR) regulates numerous important physiological functions, but its activation by diverse A(2B)AR agonists is poorly profiled. We probed potential partial and/or biased agonism in cell lines expressing variable levels of endogenous or recombinant A(2B)AR. In cAMP accumulation assays, both 5'-substituted NECA and C2-substituted MRS3997 are full agonists. However, only 5'-substituted adenosine analogs are full agonists in calcium mobilization, ERK1/2 phosphorylation and ß-arrestin translocation. A(2B)AR overexpression in HEK293 cells markedly increased the agonist potency and maximum effect in cAMP accumulation, but less in calcium and ERK1/2. A(2B)AR siRNA silencing was more effective in reducing the maximum cAMP effect of non-nucleoside agonist BAY60-6583 than NECA's. A quantitative 'operational model' characterized C2-substituted MRS3997 as either balanced (cAMP accumulation, ERK1/2) or strongly biased agonist (against calcium, ß-arrestin). N6-substitution biased against ERK1/2 (weakly) and calcium and ß-arrestin (strongly) pathways. BAY60-6583 is ERK1/2-biased, suggesting a mechanism distinct from adenosine derivatives. BAY60-6583, as A(2B)AR antagonist in MIN-6 mouse pancreatic ß cells expressing low A(2B)AR levels, induced insulin release. This is the first relatively systematic study of structure-efficacy relationships of this emerging drug target.
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Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Subunidades alfa de la Proteína de Unión al GTP Gs
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Receptor de Adenosina A2B
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Agonismo Parcial de Drogas
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Agonistas del Receptor de Adenosina A2
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Modelos Biológicos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Humans
Idioma:
En
Revista:
Biochem Pharmacol
Año:
2014
Tipo del documento:
Article