ArticleProceedings of the National Academy of Sciences of the United States of America2015
N-linked glycosylation of protease-activated receptor-1 at extracellular loop 2 regulates G-protein signaling bias.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 61 citations in OpenAlex.
- Constitutive activity among orphan G protein-coupled receptors: Molecular mechanisms and pharmacological perspectives.Molecular pharmacology · 2026Review
- Domain-specific N-glycosylation of the adhesion G-protein-coupled receptor ADGRG6 N-terminal fragment regulates trafficking, proteolytic processing, and signaling.Molecular biology of the cell · 2025Article
- Functional Divergence for N-Linked Glycosylation Sites in Equine Lutropin/Choriogonadotropin Receptors.Current issues in molecular biology · 2025Article
- The N-Linked Glycosylation Site N201 in eel Lutropin/Choriogonadotropin Receptor Is Uniquely Indispensable for cAMP Responsiveness and Receptor Surface Loss, but Not pERK1/2 Activity.Current issues in molecular biology · 2025Article
- Effects of two different variants in theFrontiers in immunology · 2025Article
- Direct interrogation of context-dependent GPCR activity with a universal biosensor platform.Cell · 2024Article
- Thrombomodulin Switches Signaling and Protease-Activated Receptor 1 Cleavage Specificity of Thrombin.Arteriosclerosis, thrombosis, and vascular biology · 2024Article
- Direct interrogation of context-dependent GPCR activity with a universal biosensor platform.bioRxiv : the preprint server for biology · 2024Article
- Protease-activated receptors in health and disease.Physiological reviews · 2023Review
- tANCHOR fast and cost-effective cell-based immunization approach with focus on the receptor-binding domain of SARS-CoV-2.Biology methods & protocols · 2023Article
- Diversification of PAR signaling through receptor crosstalk.Cellular & molecular biology letters · 2022Review
- Tunicamycin Protects against LPS-Induced Lung Injury.Pharmaceuticals (Basel, Switzerland) · 2022Article
- Review
- Role of N-Linked Glycosylation in PKR2 Trafficking and Signaling.Frontiers in neuroscience · 2021Article
- Post-Translational Modifications of G Protein-Coupled Receptors Control Cellular Signaling Dynamics in Space and Time.Pharmacological reviews · 2021Review
- Asn-linked N-acetylglucosamine of the amylin receptor 2 extracellular domain enhances peptide ligand affinity.FEBS open bio · 2021Article
- The domino effect triggered by the tethered ligand of the protease activated receptors.Thrombosis research · 2020Review
- Antigen Design for Successful Isolation of Highly Challenging Therapeutic Anti-GPCR Antibodies.International journal of molecular sciences · 2020Review
- G Protein-Coupled Receptors in the Sweet Spot: Glycosylation and other Post-translational Modifications.ACS pharmacology & translational science · 2020Review
- Calcitonin Receptor N-Glycosylation Enhances Peptide Hormone Affinity by Controlling Receptor Dynamics.Journal of molecular biology · 2020Article
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 1 country.
Funding
Abstract
Protease-activated receptor-1 (PAR1) is a G-protein-coupled receptor (GPCR) for the coagulant protease thrombin. Similar to other GPCRs, PAR1 is promiscuous and couples to multiple heterotrimeric G-protein subtypes in the same cell and promotes diverse cellular responses. The molecular mechanism by which activation of a given GPCR with the same ligand permits coupling to multiple G-protein subtypes is unclear. Here, we report that N-linked glycosylation of PAR1 at extracellular loop 2 (ECL2) controls G12/13 versus Gq coupling specificity in response to thrombin stimulation. A PAR1 mutant deficient in glycosylation at ECL2 was more effective at stimulating Gq-mediated phosphoinositide signaling compared with glycosylated wildtype receptor. In contrast, wildtype PAR1 displayed a greater efficacy at G12/13-dependent RhoA activation compared with mutant receptor lacking glycosylation at ECL2. Endogenous PAR1 rendered deficient in glycosylation using tunicamycin, a glycoprotein synthesis inhibitor, also exhibited increased PI signaling and diminished RhoA activation opposite to native receptor. Remarkably, PAR1 wildtype and glycosylation-deficient mutant were equally effective at coupling to Gi and β-arrestin-1. Consistent with preferential G12/13 coupling, thrombin-stimulated PAR1 wildtype strongly induced RhoA-mediated stress fiber formation compared with mutant receptor. In striking contrast, glycosylation-deficient PAR1 was more effective at increasing cellular proliferation, associated with Gq signaling, than wildtype receptor. These studies suggest that N-linked glycosylation at ECL2 contributes to the stabilization of an active PAR1 state that preferentially couples to G12/13 versus Gq and defines a previously unidentified function for N-linked glycosylation of GPCRs in regulating G-protein signaling bias.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.