| Autor: |
Weston, C., Lu, J., Li, N., Barkan, K., Richards, G.O., Roberts, D.J., Skerry, T.M., Poyner, D., Pardamwar, M., Reynolds, C.A., Dowell, S.J., Willars, G.B., Ladds, G. |
| Jazyk: |
angličtina |
| Rok vydání: |
2015 |
| Předmět: |
|
| ISSN: |
0021-9258 |
| Popis: |
The glucagon and glucagon-like peptide-1 (GLP-1) receptors\ud play important, opposing roles in regulating blood glucose levels.\ud Consequently, these receptors have been identified as targets\ud for novel diabetes treatments. However, drugs acting at the\ud GLP-1 receptor, although having clinical efficacy, have been\ud associated with severe adverse side-effects, and targeting of the\ud glucagon receptor has yet to be successful. Here we use a combination\ud of yeast reporter assays and mammalian systems to\ud provide a more complete understanding of glucagon receptor\ud signaling, considering the effect of multiple ligands, association\ud with the receptor-interacting protein receptor activity-modifying\ud protein-2 (RAMP2), and the role of individual G protein\ud -subunits. We demonstrate that RAMP2 alters both ligand\ud selectivity and G protein preference of the glucagon receptor.\ud Importantly, we also uncover novel cross-reactivity of therapeutically\ud used GLP-1 receptor ligands at the glucagon receptor that\ud is abolished by RAMP2 interaction. This study reveals the glucagon\ud receptor as a previously unidentified target for GLP-1\ud receptor agonists and highlights a role for RAMP2 in regulating\ud its pharmacology. Such previously unrecognized functions of\ud RAMPs highlight the need to consider all receptor-interacting\ud proteins in future drug development.\ud |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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