ArticleBritish journal of pharmacology2014
Effect of a toggle switch mutation in TM6 of the human adenosine A₃ receptor on Gi protein-dependent signalling and Gi-independent receptor internalization.
Article in British journal of pharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 34 citations in OpenAlex.
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- Covalently Binding Adenosine APurinergic signalling · 2024Article
- Species dependence of APurinergic signalling · 2023Review
- All-Atom Molecular Dynamics Simulations Indicated the Involvement of a Conserved Polar Signaling Channel in the Activation Mechanism of the Type I Cannabinoid Receptor.International journal of molecular sciences · 2023Article
- Cryo-EM structure of G-protein-coupled receptor GPR17 in complex with inhibitory G protein.MedComm · 2022Article
- Universal Properties and Specificities of the βInternational journal of molecular sciences · 2021Article
- Efficient G protein coupling is not required for agonist-mediated internalization and membrane reorganization of the adenosine AFASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2021Article
- In Silico Drug Design for Purinergic GPCRs: Overview on Molecular Dynamics Applied to Adenosine and P2Y Receptors.Biomolecules · 2020Review
- Truncated (N)-Methanocarba Nucleosides as Partial Agonists at Mouse and Human AJournal of medicinal chemistry · 2020Article
- NanoBiT Complementation to Monitor Agonist-Induced Adenosine ASLAS discovery : advancing life sciences R & D · 2020Article
- AJournal of computer-aided molecular design · 2019Article
- Complex Formation between VEGFR2 and the βCell chemical biology · 2019Article
- Fentanyl Family at the Mu-Opioid Receptor: Uniform Assessment of Binding and Computational Analysis.Molecules (Basel, Switzerland) · 2019Article
- A non-functional galanin receptor-2 in a multiple sclerosis patient.The pharmacogenomics journal · 2019Article
- Distinct but overlapping binding sites of agonist and antagonist at the relaxin family peptide 3 (RXFP3) receptor.The Journal of biological chemistry · 2018Article
- AMedicinal research reviews · 2018Review
- Designing Safer Analgesics via μ-Opioid Receptor Pathways.Trends in pharmacological sciences · 2017Review
- Drug Binding Poses Relate Structure with Efficacy in the μ Opioid Receptor.Journal of molecular biology · 2017Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
background and purposeThe highly conserved tryptophan (W6.48) in transmembrane domain 6 of GPCRs has been shown to play a central role in forming an active conformation in response to agonist binding. We set out to characterize the effect of this mutation on the efficacy of two agonists at multiple signalling pathways downstream of the adenosine A₃ receptor. EXPERIMENTAL APPROACH: Residue W6.48 in the human adenosine A₃ receptor fused to yellow fluorescent protein was mutated to phenylalanine and expressed in CHO-K1 cells containing a cAMP response element reporter gene. The effects on agonist-mediated receptor internalization were monitored by automated confocal microscopy and image analysis. Further experiments were carried out to investigate agonist-mediated ERK1/2 phosphorylation, inhibition of [(3)H]-cAMP accumulation and β-arrestin2 binding. KEY
resultsNECA was able to stimulate agonist-mediated internalization of the W6.48F mutant receptor, while the agonist HEMADO was inactive. Investigation of other downstream signalling pathways indicated that G-protein coupling was impaired for both agonists tested. Mutation of W6.48F therefore resulted in differential effects on agonist efficacy, and introduced signalling pathway bias for HEMADO at the adenosine A3 receptor. CONCLUSIONS AND IMPLICATIONS: Investigation of the pharmacology of the W6.48F mutant of the adenosine A₃ receptor confirms that this region is important in forming the active conformation of the receptor for stimulating a number of different signalling pathways and that mutations in this residue can lead to changes in agonist efficacy and signalling bias.
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