LEAP2 Impairs the Capability of the Growth Hormone Secretagogue Receptor to Regulate the Dopamine 2 Receptor Signaling

MUSTAFÁ, EMILIO R.; CORDISCO GONZÁLEZ, SANTIAGO; DAMIAN, MARJORIE; CANTEL, SONIA; DENOYELLE, SEVERINE; WAGNER, RENAUD; SCHIÖTH, HELGI B.; FEHRENTZ, JEAN-ALAIN; BANÈRES, JEAN-LOUIS; PERELLÓ, MARIO; RAINGO, JESICA

Frontiers in Pharmacology

Frontiers Editoral

Lugar: Lausanne; Año: 2021 vol. 12

The growth hormone secretagogue receptor (GHSR) signals in response to ghrelin, butalso acts via ligand-independent mechanisms that include either constitutive activation orinteraction 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(CaV2.2). Recently, the liver-expressed antimicrobial peptide 2 (LEAP2) was recognized asa novel GHSR ligand, but the mechanism of action of LEAP2 on GHSR is not wellunderstood. Here, we investigated the role of LEAP2 on the canonical and non-canonicalmodes of action of GHSR on CaV2.2 function. Using a heterologous expression systemand patch-clamp recordings, we found that LEAP2 impairs the reduction of CaV2.2currents induced by ghrelin-evoked and constitutive GHSR activities, acting as a GHSRantagonist and inverse agonist, respectively. We also found that LEAP2 prevents GHSRfrom modulating the effects of D2R signaling on CaV2.2 currents, and that the GHSRbindingN-terminal region LEAP2 underlies these effects. Using purified labeled receptorsassembled into lipid nanodiscs and Forster Resonance Energy Transfer (FRET)assessments, we found that the N-terminal region of LEAP2 stabilizes an inactiveconformation of GHSR that is dissociated from Gq protein and, consequently, reversesthe effect of GHSR on D2R-dependent Gi activation. Thus, our results provide criticalmolecular insights into the mechanism mediating LEAP2 modulation of GHSR.