LEAP2 Impairs the Capability of the Growth Hormone Secretagogue Receptor to Regulate the Dopamine 2 Receptor Signaling.
Fiche publication
Date publication
janvier 2021
Journal
Frontiers in pharmacology
Auteurs
Membres identifiés du Cancéropôle Est :
Dr WAGNER Renaud
Tous les auteurs :
Mustafá ER, Cordisco González S, Damian M, Cantel S, Denoyelle S, Wagner R, Schiöth HB, Fehrentz JA, Banères JL, Perelló M, Raingo J
Lien Pubmed
Résumé
The growth hormone secretagogue receptor (GHSR) signals in response to ghrelin, but also acts via ligand-independent mechanisms that include either constitutive activation or interaction with other G protein-coupled receptors, such as the dopamine 2 receptor (D2R). A key target of GHSR in neurons is voltage-gated calcium channels type 2.2 (Ca2.2). Recently, the liver-expressed antimicrobial peptide 2 (LEAP2) was recognized as a novel GHSR ligand, but the mechanism of action of LEAP2 on GHSR is not well understood. Here, we investigated the role of LEAP2 on the canonical and non-canonical modes of action of GHSR on Ca2.2 function. Using a heterologous expression system and patch-clamp recordings, we found that LEAP2 impairs the reduction of Ca2.2 currents induced by ghrelin-evoked and constitutive GHSR activities, acting as a GHSR antagonist and inverse agonist, respectively. We also found that LEAP2 prevents GHSR from modulating the effects of D2R signaling on Ca2.2 currents, and that the GHSR-binding N-terminal region LEAP2 underlies these effects. Using purified labeled receptors assembled into lipid nanodiscs and Forster Resonance Energy Transfer (FRET) assessments, we found that the N-terminal region of LEAP2 stabilizes an inactive conformation of GHSR that is dissociated from Gq protein and, consequently, reverses the effect of GHSR on D2R-dependent Gi activation. Thus, our results provide critical molecular insights into the mechanism mediating LEAP2 modulation of GHSR.
Mots clés
Cav2.2, GPCR, constitutive activity, dopamine receptor, ghrelin receptor, heterodimerization
Référence
Front Pharmacol. 2021 ;12:712437