Pertussis Toxin-sensitive Signaling of Melanocortin-4 Receptors in Hypothalamic GT1-7 Cells Defines Agouti-related Protein as a Biased Agonist*
AUTOR(ES)
Büch, Thomas R. H.
FONTE
American Society for Biochemistry and Molecular Biology
RESUMO
Melanocortin-4 receptor (MC4R)-induced anorexigenic signaling in the hypothalamus controls body weight and energy homeostasis. So far, MC4R-induced signaling has been exclusively attributed to its coupling to Gs proteins. In line with this monogamous G protein coupling profile, most MC4R mutants isolated from obese individuals showed a reduced ability to activate Gs. However, some mutants displayed enhanced Gs coupling, suggesting that signaling pathways independent of Gs may be involved in MC4R-mediated anorexigenic signaling. Here we report that the Gs signaling-deficient MC4R-D90N mutant activates G proteins in a pertussis toxin-sensitive manner, indicating that this mutant is able to selectively interact with Gi/o proteins. Analyzing a hypothalamic cell line (GT1-7 cells), we observed activation of pertussis toxin-sensitive G proteins by the wild-type MC4R as well, reflecting multiple coupling of the MC4R to Gs and Gi/o proteins in an endogenous cell system. Surprisingly, the agouti-related protein, which has been classified as a MC4R antagonist, selectively activates Gi/o signaling in GT1-7 cells. Thus, the agouti-related protein antagonizes melanocortin-dependent Gs activation not only by competitive antagonism but additionally by initiating Gi/o protein-induced signaling as a biased agonist.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2785329Documentos Relacionados
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