ArticleInternational journal of molecular sciences2019
Towards A Molecular Understanding of The Cannabinoid Related Orphan Receptor GPR18: A Focus on Its Constitutive Activity.
Article in International journal of molecular sciences, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Metabolite-Sensing Receptors: Emerging Targets for Modulating Chronic Pain Pathways.Current issues in molecular biology · 2025Review
- N-arachidonylglycine is a caloric state-dependent circulating metabolite which regulates human CD4iScience · 2023Article
- Structure Prediction, Evaluation, and Validation of GPR18 Lipid Receptor Using Free Programs.International journal of molecular sciences · 2022Article
- Targeting CB2 and TRPV1: Computational Approaches for the Identification of Dual Modulators.Frontiers in molecular biosciences · 2022Article
- Therapeutic Exploitation of GPR18: Beyond the Cannabinoids?Journal of medicinal chemistry · 2020Review
- Computational Investigations on the Binding Mode of Ligands for the Cannabinoid-Activated G Protein-Coupled Receptor GPR18.Biomolecules · 2020Article
- Accelerating Membrane Simulations with Hydrogen Mass Repartitioning.Journal of chemical theory and computation · 2019Article
Corrections and comments
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Authors and funding
5 authors.
Funding
Abstract
The orphan G-protein coupled receptor (GPCR), GPR18, has been recently proposed as a potential member of the cannabinoid family as it recognizes several endogenous, phytogenic, and synthetic cannabinoids. Potential therapeutic applications for GPR18 include intraocular pressure, metabolic disorders, and cancer. GPR18 has been reported to have high constitutive activity, i.e., activation/signaling occurs in the absence of an agonist. This activity can be reduced significantly by the A3.39N mutation. At the intracellular (IC) ends of (transmembrane helices) TMH3 and TMH6 in GPCRs, typically, a pair of oppositely charged amino acids form a salt bridge called the "ionic lock". Breaking of this salt bridge creates an IC opening for coupling with G protein. The GPR18 "ionic lock" residues (R3.50/S6.33) can form only a hydrogen bond. In this paper, we test the hypothesis that the high constitutive activity of GPR18 is due to the weakness of its "ionic lock" and that the A3.39N mutation strengthens this lock. To this end, we report molecular dynamics simulations of wild-type (WT) GPR18 and the A3.39N mutant in fully hydrated (POPC) phophatidylcholine lipid bilayers. Results suggest that in the A3.39N mutant, TMH6 rotates and brings R3.50 and S6.33 closer together, thus strengthening the GPR18 "ionic lock".
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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 Socratic graph.