ArticleBritish journal of pharmacology2010
Structural determinants in the second intracellular loop of the human cannabinoid CB1 receptor mediate selective coupling to G(s) and G(i).
Article in British journal of pharmacology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
38 citing papers in PubMed, 1 synthesis or guideline pooled it, 66 citations in OpenAlex.
- Cannabinoid Receptors: An Update on Cell Signaling, Pathophysiological Roles and Therapeutic Opportunities in Neurological, Cardiovascular, and Inflammatory Diseases.International journal of molecular sciences · 2020Pooled it
- Type-1 Cannabinoid Receptor Promiscuous Coupling: Computational Insights into Receptor-G Protein Interaction Dynamics.International journal of molecular sciences · 2025Article
- Cannabinoid Ligand-Mediated Glycogen Depletion in Astrocytes Is Associated With Increased Intracellular Calcium, Energy Metabolism, and Membrane Dynamics.Journal of neurochemistry · 2025Article
- The Endocannabinoid System in the Development and Treatment of Obesity: Searching for New Ideas.International journal of molecular sciences · 2025Review
- Real-Time Optical Control of CB1 Receptor SignalingJournal of the American Chemical Society · 2025Article
- Structural insights into ligand recognition and G protein preferences across histamine receptors.Communications biology · 2025Article
- Balancing G protein selectivity and efficacy in the adenosine ANature chemical biology · 2025Article
- Structural basis of tethered agonism and G protein coupling of protease-activated receptors.Cell research · 2024Article
- Cholesterol-dependent dynamic changes in the conformation of the type 1 cholecystokinin receptor affect ligand binding and G protein coupling.PLoS biology · 2024Article
- Molecular mechanism of muscarinic acetylcholine receptor M3 interaction with Gq.Communications biology · 2024Article
- Follicle-stimulating hormone orchestrates glucose-stimulated insulin secretion of pancreatic islets.Nature communications · 2023Article
- Structural insights into the human niacin receptor HCA2-GNature communications · 2023Article
- Recent Advances in Endocannabinoid System Targeting for Improved Specificity: Strategic Approaches to Targeted Drug Delivery.International journal of molecular sciences · 2022Review
- Regulation of glutamate homeostasis in the nucleus accumbens by astrocytic CB1 receptors and its role in cocaine-motivated behaviors.Addiction neuroscience · 2022Article
- Characterization of hypotensive and vasorelaxant effects of PHAR-DBH-Me a new cannabinoid receptor agonist.The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology · 2022Article
- Identification and characterization of novel compound heterozygous variants inFrontiers in endocrinology · 2022Article
- Exo- and Endo-cannabinoids in Depressive and Suicidal Behaviors.Frontiers in psychiatry · 2021Review
- Allosteric modulation of adenosine A1 and cannabinoid 1 receptor signaling by G-peptides.Pharmacology research & perspectives · 2020Article
- Cannabidiol (CBD) as a Promising Anti-Cancer Drug.Cancers · 2020Review
- Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
Abstract
background and purposeThe cannabinoid CB(1) receptor is primarily thought to be functionally coupled to the G(i) form of G proteins, through which it negatively regulates cAMP accumulation. Here, we investigated the dual coupling properties of CB(1) receptors and characterized the structural determinants that mediate selective coupling to G(s) and G(i). EXPERIMENTAL APPROACH: A cAMP-response element reporter gene system was employed to quantitatively analyze cAMP change. CB(1)/CB(2) receptor chimeras and site-directed mutagenesis combined with functional assays and computer modelling were used to determine the structural determinants mediating selective coupling to G(s) and G(i). KEY
resultsCB(1) receptors could couple to both G(s)-mediated cAMP accumulation and G(i)-induced activation of ERK1/2 and Ca(2+) mobilization, whereas CB(2) receptors selectively coupled to G(i) and inhibited cAMP production. Using CB(1)/CB(2) chimeric receptors, the second intracellular loop (ICL2) of the CB(1) receptor was identified as primarily responsible for mediating G(s) and G(i) coupling specificity. Furthermore, mutation of Leu-222 in ICL2 to either Ala or Pro switched G protein coupling from G(s) to G(i), while to Ile or Val led to balanced coupling of the mutant receptor with G(s) and G(i) . CONCLUSIONS AND IMPLICATIONS: The ICL2 of CB(1) receptors and in particular Leu-222, which resides within a highly conserved DRY(X)(5) PL motif, played a critical role in G(s) and G(i) protein coupling and specificity. Our studies provide new insight into the mechanisms governing the coupling of CB(1) receptors to G proteins and cannabinoid-induced tolerance.
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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.