Ligand-Free Signaling of G-Protein-Coupled Receptors: Physiology, Pharmacology, and Genetics.
Molecules (Basel, Switzerland) August 31, 2023 Wolfgang Sadee 8 citations
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.