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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-08-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/17/6375 |
| _version_ | 1827727958720118784 |
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| author | Wolfgang Sadee |
| author_facet | Wolfgang Sadee |
| author_sort | Wolfgang Sadee |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T23:16:18Z |
| format | Article |
| id | doaj.art-54a30b8d9d3f4f7b990b64319e79cc96 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T23:16:18Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-54a30b8d9d3f4f7b990b64319e79cc962023-11-19T08:35:07ZengMDPI AGMolecules1420-30492023-08-012817637510.3390/molecules28176375Ligand-Free Signaling of G-Protein-Coupled Receptors: Physiology, Pharmacology, and GeneticsWolfgang Sadee0Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USAG-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.https://www.mdpi.com/1420-3049/28/17/6375GPCRsligand-free receptor signalinginverse agonistneutral antagonistμ opioid receptoropioid dependence |
| spellingShingle | Wolfgang Sadee Ligand-Free Signaling of G-Protein-Coupled Receptors: Physiology, Pharmacology, and Genetics Molecules GPCRs ligand-free receptor signaling inverse agonist neutral antagonist μ opioid receptor opioid dependence |
| 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 | GPCRs ligand-free receptor signaling inverse agonist neutral antagonist μ opioid receptor opioid dependence |
| url | https://www.mdpi.com/1420-3049/28/17/6375 |
| work_keys_str_mv | AT wolfgangsadee ligandfreesignalingofgproteincoupledreceptorsphysiologypharmacologyandgenetics |