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