Articles producció científica> Bioquímica i Biotecnologia

Differential functional selectivity and downstream signaling bias of ghrelin receptor antagonists and inverse agonists

  • Identification data

    Identifier: imarina:6389541
    Authors:
    Ramirez, VTvan Oeffelen, WEPATorres-Fuentes, CChruscicka, BDruelle, CGolubeva, AVvan de Wouw, MDinan, TGCryan, JFSchellekens, H
    Abstract:
    © FASEB. The ghrelin receptor [growth hormone secretagogue receptor (GHSR)-1a] represents a promising pharmacologic target for the treatment of metabolic disorders, including obesity and cachexia, via central appetite modulation. The GHSR-1a has a complex pharmacology, highlighted by G-protein-dependent and-independent downstream signaling pathways and high basal constitutive activity. The functional selectivity and signaling biasof many GHSR-1a-specific ligands has not been fully characterized. In this study, we investigated the pharmacologic properties of ghrelin, MK-0677, L692,585, and [D-Lys3]-growth hormone-releasing peptide-6 (Dlys), JMV2959, and [D-Arg(1),D-Phe(5),D-Trp(7, 9),Leu(11)]-substance P (SP-analog). We investigated their effect on basal GHSR-1a constitutive signaling, ligand-directed downstream GHSR-1a signaling, functional selectivity, and signaling bias. Dlys behaved as a partial antagonist with a strong bias toward GHSR-1a-b-arrestin signaling, whereas JMV2959 acted as a full unbiased GHSR-1a antagonist. Moreover, the SP-analog behaved as an inverse agonist increasing G-protein-dependent signaling, but only at high concentrations, whereas, at low concentrations, the SP-analog attenuated b-arrestin-dependent signaling. Considering the limited success in the clinical development of GHSR-1a-targeted drugs so far, these findings provide a novel insight into the pharmacologic characteristics of GHSR-1a ligands and their signaling bias, which has important implications in the design of novel, more selective GHSR-1a ligands with predictable functional outcome and selectivity for preclinical and clinical drug development.
  • Others:

    Author, as appears in the article.: Ramirez, VT; van Oeffelen, WEPA; Torres-Fuentes, C; Chruscicka, B; Druelle, C; Golubeva, AV; van de Wouw, M; Dinan, TG; Cryan, JF; Schellekens, H
    Department: Bioquímica i Biotecnologia
    URV's Author/s: Torres Fuentes, Cristina
    Keywords: Probe of dependence Gpcr Ghsr-1a gpcr ghsr-1a
    Abstract: © FASEB. The ghrelin receptor [growth hormone secretagogue receptor (GHSR)-1a] represents a promising pharmacologic target for the treatment of metabolic disorders, including obesity and cachexia, via central appetite modulation. The GHSR-1a has a complex pharmacology, highlighted by G-protein-dependent and-independent downstream signaling pathways and high basal constitutive activity. The functional selectivity and signaling biasof many GHSR-1a-specific ligands has not been fully characterized. In this study, we investigated the pharmacologic properties of ghrelin, MK-0677, L692,585, and [D-Lys3]-growth hormone-releasing peptide-6 (Dlys), JMV2959, and [D-Arg(1),D-Phe(5),D-Trp(7, 9),Leu(11)]-substance P (SP-analog). We investigated their effect on basal GHSR-1a constitutive signaling, ligand-directed downstream GHSR-1a signaling, functional selectivity, and signaling bias. Dlys behaved as a partial antagonist with a strong bias toward GHSR-1a-b-arrestin signaling, whereas JMV2959 acted as a full unbiased GHSR-1a antagonist. Moreover, the SP-analog behaved as an inverse agonist increasing G-protein-dependent signaling, but only at high concentrations, whereas, at low concentrations, the SP-analog attenuated b-arrestin-dependent signaling. Considering the limited success in the clinical development of GHSR-1a-targeted drugs so far, these findings provide a novel insight into the pharmacologic characteristics of GHSR-1a ligands and their signaling bias, which has important implications in the design of novel, more selective GHSR-1a ligands with predictable functional outcome and selectivity for preclinical and clinical drug development.
    Thematic Areas: Saúde coletiva Química Psicología Odontología Nutrição Molecular biology Medicine (miscellaneous) Medicina veterinaria Medicina iii Medicina ii Medicina i Interdisciplinar Genetics General medicine Farmacia Engenharias iv Engenharias ii Educação física Ciências biológicas iii Ciências biológicas ii Ciências biológicas i Ciências ambientais Ciências agrárias i Ciência de alimentos Cell biology Biotecnología Biotechnology Biology Biodiversidade Biochemistry & molecular biology Biochemistry Astronomia / física
    licence for use: https://creativecommons.org/licenses/by/3.0/es/
    ISSN: 08926638
    Author's mail: cristina.torres@urv.cat
    Author identifier: 0000-0002-2917-6910
    Record's date: 2024-02-11
    Papper version: info:eu-repo/semantics/submittedVersion
    Link to the original source: https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.201800655R
    Papper original source: Faseb Journal. 33 (1): 518-531
    APA: Ramirez, VT; van Oeffelen, WEPA; Torres-Fuentes, C; Chruscicka, B; Druelle, C; Golubeva, AV; van de Wouw, M; Dinan, TG; Cryan, JF; Schellekens, H (2019). Differential functional selectivity and downstream signaling bias of ghrelin receptor antagonists and inverse agonists. Faseb Journal, 33(1), 518-531. DOI: 10.1096/fj.201800655R
    Licence document URL: https://repositori.urv.cat/ca/proteccio-de-dades/
    Article's DOI: 10.1096/fj.201800655R
    Entity: Universitat Rovira i Virgili
    Journal publication year: 2019
    Publication Type: Journal Publications
  • Keywords:

    Biochemistry,Biochemistry & Molecular Biology,Biology,Biotechnology,Cell Biology,Genetics,Medicine (Miscellaneous),Molecular Biology
    Probe of dependence
    Gpcr
    Ghsr-1a
    gpcr
    ghsr-1a
    Saúde coletiva
    Química
    Psicología
    Odontología
    Nutrição
    Molecular biology
    Medicine (miscellaneous)
    Medicina veterinaria
    Medicina iii
    Medicina ii
    Medicina i
    Interdisciplinar
    Genetics
    General medicine
    Farmacia
    Engenharias iv
    Engenharias ii
    Educação física
    Ciências biológicas iii
    Ciências biológicas ii
    Ciências biológicas i
    Ciências ambientais
    Ciências agrárias i
    Ciência de alimentos
    Cell biology
    Biotecnología
    Biotechnology
    Biology
    Biodiversidade
    Biochemistry & molecular biology
    Biochemistry
    Astronomia / física
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