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Pepducin targeting the C-X-C chemokine receptor type 4 acts as a biased agonist favoring activation of the inhibitory G protein

2013; National Academy of Sciences; Volume: 110; Issue: 52 Linguagem: Inglês

10.1073/pnas.1312515110

1091-6490

Julie Quoyer, Jay M. Janz, Jiansong Luo, Yong Ren, Sylvain Armando, Viktoria Lukashova, Jeffrey Benovic, Kenneth E. Carlson, S. Hunt, Michel Bouvier,

Neuropeptides and Animal Physiology

Significance Pepducins are a class of biologics that allosterically control G protein-coupled receptor (GPCR) activity, but very little is known about their mode of action. Here, we report that ATI-2341, a pepducin targeting the C-X-C chemokine receptor type 4 (CXCR4), functions as a biased ligand, favoring Gαi activation over Gα13. Moreover, contrary to the natural CXCR4 agonist, stromal cell-derived factor-1α, ATI-2341 does not promote β-arrestin recruitment. In addition to revealing the selective signaling underlying ATI-2341 effects on hematopoietic cell mobilization, the study shows that pepducins are powerful tools offering perspectives for studying GPCR functional selectivity that could impact the development of drugs with fewer side effects.