Cargando…

Ligand-Free Signaling of G-Protein-Coupled Receptors: Physiology, Pharmacology, and Genetics

G-protein-coupled receptors (GPCRs) are ubiquitous sensors and regulators of cellular functions. Each GPCR exists in complex aggregates with multiple resting and active conformations. Designed to detect weak stimuli, GPCRs can also activate spontaneously, resulting in basal ligand-free signaling. Ag...

Descripción completa

Detalles Bibliográficos
Autor principal: Sadee, Wolfgang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10489045/
https://www.ncbi.nlm.nih.gov/pubmed/37687205
http://dx.doi.org/10.3390/molecules28176375
_version_ 1785103619682467840
author Sadee, Wolfgang
author_facet Sadee, Wolfgang
author_sort Sadee, Wolfgang
collection PubMed
description G-protein-coupled receptors (GPCRs) are ubiquitous sensors and regulators of cellular functions. Each GPCR exists in complex aggregates with multiple resting and active conformations. Designed to detect weak stimuli, GPCRs can also activate spontaneously, resulting in basal ligand-free signaling. Agonists trigger a cascade of events leading to an activated agonist-receptor G-protein complex with high agonist affinity. However, the ensuing signaling process can further remodel the receptor complex to reduce agonist affinity, causing rapid ligand dissociation. The acutely activated ligand-free receptor can continue signaling, as proposed for rhodopsin and μ opioid receptors, resulting in robust receptor activation at low agonist occupancy with enhanced agonist potency. Continued receptor stimulation can further modify the receptor complex, regulating sustained ligand-free signaling—proposed to play a role in opioid dependence. Basal, acutely agonist-triggered, and sustained elevated ligand-free signaling could each have distinct functions, reflecting multi-state conformations of GPCRs. This review addresses basal and stimulus-activated ligand-free signaling, its regulation, genetic factors, and pharmacological implications, focusing on opioid and serotonin receptors, and the growth hormone secretagogue receptor (GHSR). The hypothesis is proposed that ligand-free signaling of 5-HT2A receptors mediate therapeutic effects of psychedelic drugs. Research avenues are suggested to close the gaps in our knowledge of ligand-free GPCR signaling.
format Online
Article
Text
id pubmed-10489045
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-104890452023-09-09 Ligand-Free Signaling of G-Protein-Coupled Receptors: Physiology, Pharmacology, and Genetics Sadee, Wolfgang Molecules Review G-protein-coupled receptors (GPCRs) are ubiquitous sensors and regulators of cellular functions. Each GPCR exists in complex aggregates with multiple resting and active conformations. Designed to detect weak stimuli, GPCRs can also activate spontaneously, resulting in basal ligand-free signaling. Agonists trigger a cascade of events leading to an activated agonist-receptor G-protein complex with high agonist affinity. However, the ensuing signaling process can further remodel the receptor complex to reduce agonist affinity, causing rapid ligand dissociation. The acutely activated ligand-free receptor can continue signaling, as proposed for rhodopsin and μ opioid receptors, resulting in robust receptor activation at low agonist occupancy with enhanced agonist potency. Continued receptor stimulation can further modify the receptor complex, regulating sustained ligand-free signaling—proposed to play a role in opioid dependence. Basal, acutely agonist-triggered, and sustained elevated ligand-free signaling could each have distinct functions, reflecting multi-state conformations of GPCRs. This review addresses basal and stimulus-activated ligand-free signaling, its regulation, genetic factors, and pharmacological implications, focusing on opioid and serotonin receptors, and the growth hormone secretagogue receptor (GHSR). The hypothesis is proposed that ligand-free signaling of 5-HT2A receptors mediate therapeutic effects of psychedelic drugs. Research avenues are suggested to close the gaps in our knowledge of ligand-free GPCR signaling. MDPI 2023-08-31 /pmc/articles/PMC10489045/ /pubmed/37687205 http://dx.doi.org/10.3390/molecules28176375 Text en © 2023 by the author. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Sadee, Wolfgang
Ligand-Free Signaling of G-Protein-Coupled Receptors: Physiology, Pharmacology, and Genetics
title Ligand-Free Signaling of G-Protein-Coupled Receptors: Physiology, Pharmacology, and Genetics
title_full Ligand-Free Signaling of G-Protein-Coupled Receptors: Physiology, Pharmacology, and Genetics
title_fullStr Ligand-Free Signaling of G-Protein-Coupled Receptors: Physiology, Pharmacology, and Genetics
title_full_unstemmed Ligand-Free Signaling of G-Protein-Coupled Receptors: Physiology, Pharmacology, and Genetics
title_short Ligand-Free Signaling of G-Protein-Coupled Receptors: Physiology, Pharmacology, and Genetics
title_sort ligand-free signaling of g-protein-coupled receptors: physiology, pharmacology, and genetics
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10489045/
https://www.ncbi.nlm.nih.gov/pubmed/37687205
http://dx.doi.org/10.3390/molecules28176375
work_keys_str_mv AT sadeewolfgang ligandfreesignalingofgproteincoupledreceptorsphysiologypharmacologyandgenetics