The second extracellular loop of GPCRs determines subtype-selectivity and controls efficacy as evidenced by loop exchange study at A2 adenosine receptors

Seibt, Benjamin F.; Schiedel, Anke C.; Thimm, Dominik; Hinz, Sonja; Sherbiny, Farag F.; Müller, Christian

doi:10.1016/j.bcp.2013.03.005

Cited by 35 publications

(33 citation statements)

References 54 publications

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“…In radioligand binding studies using an antagonist radioligand (Auchampach et al, 2009;Schiedel et al, 2011;Seibt et al, 2013), BAY60-6583 showed significantly higher affinity than NECA. This was surprising given the fact that in functional assays, BAY60-6583 and NECA had been found to be almost equipotent (Peeters et al, 2011;Schiedel et al, 2011;Seibt et al, 2013;Thimm et al, 2013).…”

Section: Discussionmentioning

confidence: 98%

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BAY60-6583 Acts as a Partial Agonist at Adenosine A_2B Receptors

Hinz

Lacher

Seibt

et al. 2014

J Pharmacol Exp Ther

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phenyl]pyridin-2-yl}sulfanyl)acetamide] is the most potent and selective adenosine A 2B receptor (A 2B AR) agonist known to date. Therefore, it has been widely used for in vitro and in vivo experiments. In the present study, we investigated the binding and functional properties of BAY60-6583 in various native and recombinant cell lines with different A 2B AR expression levels. In cAMP accumulation and calcium mobilization assays, BAY60-6583 was found to be significantly less efficacious than adenosine or the adenosine derivative NECA. When it was tested in human embryonic kidney (HEK)293 cells, its efficacy correlated with the A 2B expression level of the cells. In Jurkat T cells, BAY60-6583 antagonized the agonistic effect of NECA and adenosine as determined in cAMP accumulation assays. On the basis of these results, we conclude that BAY60-6583 acts as a partial agonist at adenosine A 2B receptors. At high levels of the physiologic agonist adenosine, BAY60-6583 may act as an antagonist and block the effects of adenosine at A 2B receptors. This has to be considered when applying the A 2B -selective "agonist" BAY60-6583 in pharmacological studies, and previous research results may have to be reinterpreted.

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Section: Discussionmentioning

confidence: 98%

“…This was surprising given the fact that in functional assays, BAY60-6583 and NECA had been found to be almost equipotent (Peeters et al, 2011;Schiedel et al, 2011;Seibt et al, 2013;Thimm et al, 2013). To further examine the pharmacological profile of BAY60-6583, we performed sodium shift experiments.…”

Section: Discussionmentioning

confidence: 99%

BAY60-6583 Acts as a Partial Agonist at Adenosine A_2B Receptors

Hinz

Lacher

Seibt

et al. 2014

J Pharmacol Exp Ther

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“…This is highlighted by the high selectivity of CGS21680 for A 2A R compared with A 2B R, which is due mainly to differences in the amino acid sequences of EL2. Remarkably, replacement of EL2 in A 2B R by EL2 from A 2A R allowed the recovery of some binding affinity for CGS21680 and led to activation of heterotrimeric G protein (Seibt et al, 2013). However, defining the relative roles of individual amino acid residues in determining subtype specificity is not clear cut.…”

Section: Discussionmentioning

confidence: 99%

Molecular Determinants of CGS21680 Binding to the Human Adenosine A_2A Receptor

et al. 2015

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“…Despite these limitations, a number of GPCR structures with various antagonists, synthetic or even native agonists have become available, including some receptors appearing in GPCR dimers. Furthermore, experimental evidence has implicated the contribution of the second extracellular loop (ECL2) to ligand recognition and selectivity for a number of different GPCRs [95].…”

Section: Structural and Dynamic Insights On The Functional Impact Of mentioning

confidence: 99%

Molecular dynamics simulations and structure-based network analysis reveal structural and functional aspects of G-protein coupled receptor dimer interactions

Baltoumas

Theodoropoulou

Hamodrakas

2016

J Comput Aided Mol Des

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A significant amount of experimental evidence suggests that G-protein coupled receptors (GPCRs) do not act exclusively as monomers but also form biologically relevant dimers and oligomers. However, the structural determinants, stoichiometry and functional importance of GPCR oligomerization remain topics of intense speculation. In this study we attempted to evaluate the nature and dynamics of GPCR oligomeric interactions. A representative set of GPCR homodimers were studied through Coarse-Grained Molecular Dynamics simulations, combined with interface analysis and concepts from network theory for the construction and analysis of dynamic structural networks. Our results highlight important structural determinants that seem to govern receptor dimer interactions. A conserved dynamic behavior was observed among different GPCRs, including receptors belonging in different GPCR classes. Specific GPCR regions were highlighted as the core of the interfaces. Finally, correlations of motion were observed between parts of the dimer interface and GPCR segments participating in ligand binding and receptor activation, suggesting the existence of mechanisms through which dimer formation may affect GPCR function. The results of this study can be used to drive experiments aimed at exploring GPCR oligomerization, as well as in the study of transmembrane protein-protein interactions in general.

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The second extracellular loop of GPCRs determines subtype-selectivity and controls efficacy as evidenced by loop exchange study at A2 adenosine receptors

Cited by 35 publications

References 54 publications

BAY60-6583 Acts as a Partial Agonist at Adenosine A_2B Receptors

BAY60-6583 Acts as a Partial Agonist at Adenosine A_2B Receptors

Molecular Determinants of CGS21680 Binding to the Human Adenosine A_2A Receptor

Molecular dynamics simulations and structure-based network analysis reveal structural and functional aspects of G-protein coupled receptor dimer interactions

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The second extracellular loop of GPCRs determines subtype-selectivity and controls efficacy as evidenced by loop exchange study at A2 adenosine receptors

Cited by 35 publications

References 54 publications

BAY60-6583 Acts as a Partial Agonist at Adenosine A2B Receptors

BAY60-6583 Acts as a Partial Agonist at Adenosine A2B Receptors

Molecular Determinants of CGS21680 Binding to the Human Adenosine A2A Receptor

Molecular dynamics simulations and structure-based network analysis reveal structural and functional aspects of G-protein coupled receptor dimer interactions

Contact Info

Product

Resources

About

BAY60-6583 Acts as a Partial Agonist at Adenosine A_2B Receptors

BAY60-6583 Acts as a Partial Agonist at Adenosine A_2B Receptors

Molecular Determinants of CGS21680 Binding to the Human Adenosine A_2A Receptor