ArticleThe Journal of pharmacology and experimental therapeutics2013
Novel insights into CB1 cannabinoid receptor signaling: a key interaction identified between the extracellular-3 loop and transmembrane helix 2.
Article in The Journal of pharmacology and experimental therapeutics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 20 citations in OpenAlex.
- The NPXXY Motif Regulates β-Arrestin Recruitment by the CB1 Cannabinoid Receptor.Cannabis and cannabinoid research · 2023Article
- Pharmacological evaluation of enantiomerically separated positive allosteric modulators of cannabinoid 1 receptor, GAT591 and GAT593.Frontiers in pharmacology · 2022Article
- GPR6 Structural Insights: Homology Model Construction and Docking Studies.Molecules (Basel, Switzerland) · 2020Article
- Allosteric Modulation of Cannabinoid Receptor 1-Current Challenges and Future Opportunities.International journal of molecular sciences · 2019Review
- Identification of CB1 Receptor Allosteric Sites Using Force-Biased MMC Simulated Annealing and Validation by Structure-Activity Relationship Studies.ACS medicinal chemistry letters · 2019Article
- Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol-dimethylheptyl at the type 1 and type 2 cannabinoid receptors.British journal of pharmacology · 2019Article
- The F238L Point Mutation in the Cannabinoid Type 1 Receptor Enhances Basal Endocytosis via Lipid Rafts.Frontiers in molecular neuroscience · 2018Article
- Review
- Mapping Cannabinoid 1 Receptor Allosteric Site(s): Critical Molecular Determinant and Signaling Profile of GAT100, a Novel, Potent, and Irreversibly Binding Probe.ACS chemical neuroscience · 2016Article
- (4-(Bis(4-fluorophenyl)methyl)piperazin-1-yl)(cyclohexyl)methanone hydrochloride (LDK1229): a new cannabinoid CB1 receptor inverse agonist from the class of benzhydryl piperazine analogs.Molecular pharmacology · 2015Article
- Probing the carboxyester side chain in controlled deactivation (-)-δ(8)-tetrahydrocannabinols.Journal of medicinal chemistry · 2015Article
- Allosteric modulation of a cannabinoid G protein-coupled receptor: binding site elucidation and relationship to G protein signaling.The Journal of biological chemistry · 2014Article
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
Activation of the cannabinoid CB1 receptor (CB1) is modulated by aspartate residue D2.63(176) in transmembrane helix (TMH) 2. Interestingly, D2.63 does not affect the affinity for ligand binding at the CB1 receptor. Studies in class A G protein-coupled receptors have suggested an ionic interaction between residues of TMH2 and 7. In this report, modeling studies identified residue K373 in the extracellular-3 (EC-3) loop in charged interactions with D2.63. We investigated this possibility by performing reciprocal mutations and biochemical studies. D2.63(176)A, K373A, D2.63(176)A-K373A, and the reciprocal mutant with the interacting residues juxtaposed D2.63(176)K-K373D were characterized using radioligand binding and guanosine 5'-3-O-(thio)triphosphate functional assays. None of the mutations resulted in a significant change in the binding affinity of N-(piperidiny-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A) or (-)-3cis -[2-hydroxyl-4-(1,1-dimethyl-heptyl)phenyl]-trans-4-[3-hydroxyl-propyl] cyclohexan-1-ol (CP55,940). Modeling studies indicated that binding-site interactions and energies of interaction for CP55,940 were similar between wild-type and mutant receptors. However, the signaling of CP55,940, and (R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]-pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthalenyl)-methanone mesylate (WIN55,212-2) was impaired at the D2.63(176)A-K373A and the single-alanine mutants. In contrast, the reciprocal D2.63(176)K-K373D mutant regained function for both CP55,940 and WIN55,212-2. Computational results indicate that the D2.63(176)-K373 ionic interaction strongly influences the conformation(s) of the EC-3 loop, providing a structure-based rationale for the importance of the EC-3 loop to signal transduction in CB1. The putative ionic interaction results in the EC-3 loop pulling over the top (extracellular side) of the receptor; this EC-3 loop conformation may serve protective and mechanistic roles. These results suggest that the ionic interaction between D2.63(176) and K373 is important for CB1 signal transduction.
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