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

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...

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Detalles Bibliográficos
Autores principales: Mustafá, Emilio Román, Cordisco Gonzalez, Santiago, Damian, Marjorie, Cantel, Sonia, Denoyelle, Severine, Wagner, Renaud, Schiöth, Helgi B., Fehrentz, Jean Alain, Banères, Jean Louis, Perelló, Mario Carlos, Raingo, Jesica
Formato: Articulo
Lenguaje:Inglés
Publicado: 2021
Materias:
Biología
Bioquímica
GPCR
Heterodimerization
Cav2.2
Ghrelin receptor
Dopamine receptor
Constitutive activity
Acceso en línea:http://sedici.unlp.edu.ar/handle/10915/130011
Aporte de:
SEDICI (UNLP) de Universidad Nacional de La Plata
id I19-R120-10915-130011
record_format dspace
institution Universidad Nacional de La Plata
institution_str I-19
repository_str R-120
collection SEDICI (UNLP)
language Inglés
topic Biología
Bioquímica
GPCR
Heterodimerization
Cav2.2
Ghrelin receptor
Dopamine receptor
Constitutive activity
spellingShingle Biología
Bioquímica
GPCR
Heterodimerization
Cav2.2
Ghrelin receptor
Dopamine receptor
Constitutive activity
Mustafá, Emilio Román
Cordisco Gonzalez, Santiago
Damian, Marjorie
Cantel, Sonia
Denoyelle, Severine
Wagner, Renaud
Schiöth, Helgi B.
Fehrentz, Jean Alain
Banères, Jean Louis
Perelló, Mario Carlos
Raingo, Jesica
LEAP2 Impairs the Capability of the Growth Hormone Secretagogue Receptor to Regulate the Dopamine 2 Receptor Signaling
topic_facet Biología
Bioquímica
GPCR
Heterodimerization
Cav2.2
Ghrelin receptor
Dopamine receptor
Constitutive activity
description 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 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 on CaV2.2 currents, and that the GHSRbinding 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.
format Articulo
Articulo
author Mustafá, Emilio Román
Cordisco Gonzalez, Santiago
Damian, Marjorie
Cantel, Sonia
Denoyelle, Severine
Wagner, Renaud
Schiöth, Helgi B.
Fehrentz, Jean Alain
Banères, Jean Louis
Perelló, Mario Carlos
Raingo, Jesica
author_facet Mustafá, Emilio Román
Cordisco Gonzalez, Santiago
Damian, Marjorie
Cantel, Sonia
Denoyelle, Severine
Wagner, Renaud
Schiöth, Helgi B.
Fehrentz, Jean Alain
Banères, Jean Louis
Perelló, Mario Carlos
Raingo, Jesica
author_sort Mustafá, Emilio Román
title LEAP2 Impairs the Capability of the Growth Hormone Secretagogue Receptor to Regulate the Dopamine 2 Receptor Signaling
title_short LEAP2 Impairs the Capability of the Growth Hormone Secretagogue Receptor to Regulate the Dopamine 2 Receptor Signaling
title_full LEAP2 Impairs the Capability of the Growth Hormone Secretagogue Receptor to Regulate the Dopamine 2 Receptor Signaling
title_fullStr LEAP2 Impairs the Capability of the Growth Hormone Secretagogue Receptor to Regulate the Dopamine 2 Receptor Signaling
title_full_unstemmed LEAP2 Impairs the Capability of the Growth Hormone Secretagogue Receptor to Regulate the Dopamine 2 Receptor Signaling
title_sort leap2 impairs the capability of the growth hormone secretagogue receptor to regulate the dopamine 2 receptor signaling
publishDate 2021
url http://sedici.unlp.edu.ar/handle/10915/130011
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