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

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

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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 (CaV2.2).Recently, the liver-expressed antimicrobial peptide 2 (LEAP2) was recognized as here 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 CaV2.2 function.Using a heterologous expression system and patch-clamp recordings, we found that LEAP2 impairs the reduction of CaV2.2 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 feline 1-hcpch vaccine on CaV2.

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.