Review
Version 1
Preserved in Portico This version is not peer-reviewed
Ligand-Free Signaling of G Protein Coupled Receptors: Physiology, Pharmacology, and Genetics
Version 1
: Received: 9 August 2023 / Approved: 10 August 2023 / Online: 10 August 2023 (09:48:03 CEST)
A peer-reviewed article of this Preprint also exists.
Sadee, W. Ligand-Free Signaling of G-Protein-Coupled Receptors: Physiology, Pharmacology, and Genetics. Molecules 2023, 28, 6375. Sadee, W. Ligand-Free Signaling of G-Protein-Coupled Receptors: Physiology, Pharmacology, and Genetics. Molecules 2023, 28, 6375.
Abstract
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 activate 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 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). Ligand-free signaling of intracellular 5-HT2A receptors could mediate therapeutic effects of psychedelic drugs. Research avenues are suggested to close gaps in our knowledge of ligand-free GPCR signaling.
Keywords
ligand-free receptor signaling; inverse agonist; neutral antagonist; μ opioid receptor; opioid dependence; 6β-naltrexol; psychedelics; LSD; 5-HT2A; GHSR
Subject
Medicine and Pharmacology, Medicine and Pharmacology
Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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