Internalization and desensitization of the human glucose-dependent-insulinotropic receptor is affected by N-terminal acetylation of the agonist

Sadek Ismail, Ingrid Dubois-Vedrenne, Marie Laval, Irina G. Tikhonova, Romina D'Angelo, Claire Sanchez, Pascal Clerc, Marie-Julie Gherardi, Véronique Gigoux, Remi Magnan, Daniel Fourmy

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18 Citations (Scopus)
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Abstract

How incretins regulate presence of their receptors at the cell surface and their activity is of paramount importance for the development of therapeutic strategies targeting these receptors. We have studied internalization of the human Glucose-Insulinotropic Polypeptide receptor (GIPR). GIP stimulated rapid robust internalization of the GIPR, the major part being directed to lysosomes. GIPR internalization involved mainly clathrin-coated pits, AP-2 and dynamin. However, neither GIPR C-terminal region nor β-arrestin1/2 was required. Finally, N-acetyl-GIP recognized as a dipeptidyl-IV resistant analogue, fully stimulated cAMP production with a ∼15-fold lower potency than GIP and weakly stimulated GIPR internalization and desensitization of cAMP response. Furthermore, docking N-acetyl-GIP in the binding site of modelled GIPR showed slighter interactions with residues of helices 6 and 7 of GIPR compared to GIP. Therefore, incomplete or partial activity of N-acetyl-GIP on signaling involved in GIPR desensitization and internalization contributes to the enhanced incretin activity of this peptide.

Original languageEnglish
Pages (from-to)202-215
Number of pages14
JournalMolecular and Cellular Endocrinology
Volume414
Early online date28 Jul 2015
DOIs
Publication statusPublished - 15 Oct 2015

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