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...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2021-08-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2021.712437/full |
| _version_ | 1818456503489658880 |
|---|---|
| author | Emilio R. Mustafá Santiago Cordisco González Marjorie Damian Sonia Cantel Severine Denoyelle Renaud Wagner Helgi B. Schiöth Helgi B. Schiöth Jean-Alain Fehrentz Jean-Louis Banères Mario Perelló Jesica Raingo |
| author_facet | Emilio R. Mustafá Santiago Cordisco González Marjorie Damian Sonia Cantel Severine Denoyelle Renaud Wagner Helgi B. Schiöth Helgi B. Schiöth Jean-Alain Fehrentz Jean-Louis Banères Mario Perelló Jesica Raingo |
| author_sort | Emilio R. Mustafá |
| collection | DOAJ |
| 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 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. |
| first_indexed | 2024-12-14T22:27:42Z |
| format | Article |
| id | doaj.art-0e77ad9215a246d98475647b715d366f |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-14T22:27:42Z |
| publishDate | 2021-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-0e77ad9215a246d98475647b715d366f2022-12-21T22:45:18ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122021-08-011210.3389/fphar.2021.712437712437LEAP2 Impairs the Capability of the Growth Hormone Secretagogue Receptor to Regulate the Dopamine 2 Receptor SignalingEmilio R. Mustafá0Santiago Cordisco González1Marjorie Damian2Sonia Cantel3Severine Denoyelle4Renaud Wagner5Helgi B. Schiöth6Helgi B. Schiöth7Jean-Alain Fehrentz8Jean-Louis Banères9Mario Perelló10Jesica Raingo11Laboratory of Electrophysiology of the Multidisciplinary Institute of Cell Biology [IMBICE, Argentine Research Council (CONICET) and Scientific Research Commission, Province of Buenos Aires (CIC-PBA), National University of La Plata (UNLP)], La Plata, ArgentinaLaboratory of Electrophysiology of the Multidisciplinary Institute of Cell Biology [IMBICE, Argentine Research Council (CONICET) and Scientific Research Commission, Province of Buenos Aires (CIC-PBA), National University of La Plata (UNLP)], La Plata, ArgentinaInstitut des Biomolécules Max Mousseron (IBMM), Université Montpellier, CNRS, Montpellier, FranceInstitut des Biomolécules Max Mousseron (IBMM), Université Montpellier, CNRS, Montpellier, FranceInstitut des Biomolécules Max Mousseron (IBMM), Université Montpellier, CNRS, Montpellier, FrancePlateforme IMPReSs, CNRS UMR7242, Biotechnologie et Signalisation Cellulaire, École Supérieure de Biotechnologie de Strasbourg, Strasbourg, FranceDepartment of Neuroscience, Uppsala University, Uppsala, SwedenInstitute for Translational Medicine and Biothechnology, I. M. Sechenov First Moscow State Medical University, Moscow, RussiaInstitut des Biomolécules Max Mousseron (IBMM), Université Montpellier, CNRS, Montpellier, FranceInstitut des Biomolécules Max Mousseron (IBMM), Université Montpellier, CNRS, Montpellier, FranceLaboratory of Neurophysiology of the Multidisciplinary Institute of Cell Biology [IMBICE, Argentine Research Council (CONICET) and Scientific Research Commission, Province of Buenos Aires (CIC-PBA), National University of La Plata (UNLP)], La Plata, ArgentinaLaboratory of Electrophysiology of the Multidisciplinary Institute of Cell Biology [IMBICE, Argentine Research Council (CONICET) and Scientific Research Commission, Province of Buenos Aires (CIC-PBA), National University of La Plata (UNLP)], La Plata, ArgentinaThe 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 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.https://www.frontiersin.org/articles/10.3389/fphar.2021.712437/fullGPCRheterodimerizationCav2.2ghrelin receptordopamine receptorconstitutive activity |
| spellingShingle | Emilio R. Mustafá Santiago Cordisco González Marjorie Damian Sonia Cantel Severine Denoyelle Renaud Wagner Helgi B. Schiöth Helgi B. Schiöth Jean-Alain Fehrentz Jean-Louis Banères Mario Perelló Jesica Raingo LEAP2 Impairs the Capability of the Growth Hormone Secretagogue Receptor to Regulate the Dopamine 2 Receptor Signaling Frontiers in Pharmacology GPCR heterodimerization Cav2.2 ghrelin receptor dopamine receptor constitutive activity |
| title | 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_short | 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 |
| topic | GPCR heterodimerization Cav2.2 ghrelin receptor dopamine receptor constitutive activity |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2021.712437/full |
| work_keys_str_mv | AT emiliormustafa leap2impairsthecapabilityofthegrowthhormonesecretagoguereceptortoregulatethedopamine2receptorsignaling AT santiagocordiscogonzalez leap2impairsthecapabilityofthegrowthhormonesecretagoguereceptortoregulatethedopamine2receptorsignaling AT marjoriedamian leap2impairsthecapabilityofthegrowthhormonesecretagoguereceptortoregulatethedopamine2receptorsignaling AT soniacantel leap2impairsthecapabilityofthegrowthhormonesecretagoguereceptortoregulatethedopamine2receptorsignaling AT severinedenoyelle leap2impairsthecapabilityofthegrowthhormonesecretagoguereceptortoregulatethedopamine2receptorsignaling AT renaudwagner leap2impairsthecapabilityofthegrowthhormonesecretagoguereceptortoregulatethedopamine2receptorsignaling AT helgibschioth leap2impairsthecapabilityofthegrowthhormonesecretagoguereceptortoregulatethedopamine2receptorsignaling AT helgibschioth leap2impairsthecapabilityofthegrowthhormonesecretagoguereceptortoregulatethedopamine2receptorsignaling AT jeanalainfehrentz leap2impairsthecapabilityofthegrowthhormonesecretagoguereceptortoregulatethedopamine2receptorsignaling AT jeanlouisbaneres leap2impairsthecapabilityofthegrowthhormonesecretagoguereceptortoregulatethedopamine2receptorsignaling AT marioperello leap2impairsthecapabilityofthegrowthhormonesecretagoguereceptortoregulatethedopamine2receptorsignaling AT jesicaraingo leap2impairsthecapabilityofthegrowthhormonesecretagoguereceptortoregulatethedopamine2receptorsignaling |