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

G-protein-coupled receptors (GPCRs) can signal even without a ligand bound, a phenomenon called ligand-free or basal signaling. Agonists trigger signaling that can remodel the receptor, causing rapid ligand dissociation while the receptor continues to signal. This acutely activated, ligand-free signaling may enhance agonist potency at low occupancy. Sustained elevated ligand-free signaling is proposed to play a role in opioid dependence. The review focuses on opioid, serotonin, and growth hormone secretagogue receptors, and hypothesizes that ligand-free signaling of 5-HT2A receptors mediates therapeutic effects of psychedelic drugs. Research avenues are suggested to fill knowledge gaps.

Study at a glance

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 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.