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Article Dans Une Revue FASEB Journal Année : 2014

Biased signaling through G-protein-coupled PROKR2 receptors harboring missense mutations

Résumé

Various missense mutations in the gene coding for prokineticin receptor 2 (PROKR2), a G-protein-coupled receptor, have been identified in patients with Kallmann syndrome. However, the functional consequences of these mutations on the different signaling pathways of this receptor have not been studied. We first showed that the wild-type PROKR2 can activate different G-protein subtypes (Gq, Gs, and Gi/o) and recruit beta-arrestins in transfected HEK-293 cells. We then examined, for each of these signaling pathways, the effects of 9 mutations that did not significantly impair cell surface targeting or ligand binding of the receptor. Four mutant receptors showing defective Gq signaling (R85C, R85H, R164Q, and V331M) could still recruit beta-arrestins on ligand activation, which may cause biased signaling in vivo. Conversely, the R80C receptor could activate the 3 types of G proteins but could not recruit beta-arrestins. Finally, the R268C receptor could recruit beta-arrestins and activate the Gq and Gs signaling pathways but could not activate the Gi/o signaling pathway. Our results validate the concept that mutations in the genes encoding membrane receptors can bias downstream signaling in various ways, possibly leading to pathogenic and, perhaps in some cases, protective (e.g., R268C) effects.
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Dates et versions

hal-01942940 , version 1 (03-12-2018)

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Citer

Oualid Sbai, Carine Monnier, Catherine Dode, Jean-Philippe Pin, Jean-Pierre Hardelin, et al.. Biased signaling through G-protein-coupled PROKR2 receptors harboring missense mutations. FASEB Journal, 2014, 28 (8), pp.3734--44. ⟨10.1096/fj.13-243402⟩. ⟨hal-01942940⟩
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