ArticleMolecular pharmacology2009
Stereochemistry of an agonist determines coupling preference of beta2-adrenoceptor to different G proteins in cardiomyocytes.
Article in Molecular pharmacology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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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
48 citing papers in PubMed, 80 citations in OpenAlex.
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- Biased β2-adrenoceptor signalling in heart failure: pathophysiology and drug discovery.British journal of pharmacology · 2015Review
- Advances in receptor conformation research: the quest for functionally selective conformations focusing on the β2-adrenoceptor.British journal of pharmacology · 2015Review
- Interaction of fenoterol stereoisomers with β2-adrenoceptor-G sα fusion proteins: antagonist and agonist competition binding.Naunyn-Schmiedeberg's archives of pharmacology · 2015Article
- Structure-bias relationships for fenoterol stereoisomers in six molecular and cellular assays at the β2-adrenoceptor.Naunyn-Schmiedeberg's archives of pharmacology · 2015Article
- Tyrosine 308 is necessary for ligand-directed Gs protein-biased signaling of β2-adrenoceptor.The Journal of biological chemistry · 2014Article
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- Comparative molecular field analysis of fenoterol derivatives interacting with an agonist-stabilized form of the β₂-adrenergic receptor.Bioorganic & medicinal chemistry · 2014Article
- β2-Adrenoceptor-mediated regulation of glucose uptake in skeletal muscle--ligand-directed signalling or a reflection of system complexity?Naunyn-Schmiedeberg's archives of pharmacology · 2013Article
- Regulation of G protein subunit composition in cardiomyocytes: pharmacological implications.Naunyn-Schmiedeberg's archives of pharmacology · 2013Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 2 countries.
Funding
Abstract
A fundamental question regarding receptor-G protein interaction is whether different agonists can lead a receptor to different intracellular signaling pathways. Our previous studies have demonstrated that although most beta(2)-adrenoceptor agonists activate both G(s) and G(i) proteins, fenoterol, a full agonist of beta(2)-adrenoceptor, selectively activates G(s) protein. Fenoterol contains two chiral centers and may exist as four stereoisomers. We have synthesized a series of stereoisomers of fenoterol and its derivatives and characterized their receptor binding and pharmacological properties. We tested the hypothesis that the stereochemistry of an agonist determines selectivity of receptor coupling to different G protein(s). We found that the R,R isomers of fenoterol and methoxyfenoterol exhibited more potent effects to increase cardiomyocyte contraction than their S,R isomers. It is noteworthy that although (R,R)-fenoterol and (R,R)-methoxyfenoterol preferentially activate G(s) signaling, their S,R isomers were able to activate both G(s) and G(i) proteins as evidenced by the robust pertussis toxin sensitivities of their effects on cardiomyocyte contraction and on phosphorylation of extracellular signal-regulated kinase 1/2. The differential G protein selectivities of the fenoterol stereoisomers were further confirmed by photoaffinity labeling studies on G(s),G(i2), and G(i3) proteins. The inefficient G(i) signaling with the R,R isomers is not caused by the inability of the R,R isomers to trigger the protein kinase A (PKA)-mediated phosphorylation of the beta(2)-adrenoceptor, because the R,R isomers also markedly increased phosphorylation of the receptor at serine 262 by PKA. We conclude that in addition to receptor subtype and phosphorylation status, the stereochemistry of a given agonist plays an important role in determining receptor-G protein selectivity and downstream signaling events.
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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.