Related Experiment Video
Updated: Jan 21, 2026
Quantifying Agonist Activity at G Protein-coupled Receptors
Published on: December 26, 2011
Agonists activate different A2B adenosine receptor signaling pathways in MBA-MD-231 breast cancer cells with distinct
Marthe Koussémou1, Karl-Norbert Klotz2
1Institut für Pharmakologie und Toxikologie, Universität Würzburg, Versbacher Str. 9, 97078, Würzburg, Germany.
Abstract:
It is well established that some receptor types including G protein-coupled receptors may transduce effects through more than one signaling pathway. This holds also true for A2B adenosine receptors which were shown to trigger an increase in intracellular Ca2+ levels in addition to the canonical stimulation of adenylyl cyclase. We have recently shown that activation of A2B receptors in the breast cancer cell line MBA-MD-231 elicits a reduction in ERK1/2 phosphorylation, an effect that might be exploited in treatment of cancer cell growth and proliferation. In this study, we investigate whether structurally divers agonists show functional selectivity for any of the signaling pathways leading to an increase of intracellular cAMP or Ca2+, or the reduction of ERK1/2 phosphorylation. As agonists, adenosine derivatives were used bearing different substitutions in 2- and 6-position and, in addition, a ligand with a non-nucleoside structure was tested. It was found that all the tested ligands showed similar pharmacological profiles for the three responses investigated in MBA-MD-231 cells. However, the reduction of ERK1/2 phosphorylation occurred with 40-500-fold higher potency compared to stimulation of adenylyl cyclase or increasing intracellular Ca2+ levels. Based on these observations, it seems possible to utilize activation of A2B adenosine receptors expressed in certain cancers to limit cell growth and proliferation due to reduction of MAPK activity without activation of other signaling pathways potentially responsible for side effects.
Insights
Activation of A2B adenosine receptors in breast cancer cells reduces ERK1/2 phosphorylation more potently than other signaling pathways. This suggests a targeted cancer therapy approach to limit growth without side effects.
Area of Science:
- Pharmacology
- Molecular Biology
- Oncology
Background:
- G protein-coupled receptors, like A2B adenosine receptors, can activate multiple signaling pathways.
- A2B adenosine receptors are known to increase intracellular Ca2+ and stimulate adenylyl cyclase.
- Previous research indicated A2B receptor activation reduces ERK1/2 phosphorylation in MBA-MD-231 breast cancer cells.
Purpose of the Study:
- To investigate functional selectivity of diverse A2B adenosine receptor agonists.
- To determine if agonists selectively activate pathways for cAMP increase, Ca2+ increase, or ERK1/2 phosphorylation reduction.
- To assess the potential of A2B receptor activation for cancer treatment.
Main Methods:
- Tested structurally diverse adenosine derivatives and a non-nucleoside ligand as agonists.
- Investigated three cellular responses: intracellular cAMP levels, intracellular Ca2+ levels, and ERK1/2 phosphorylation.
- Utilized the MBA-MD-231 breast cancer cell line.
Main Results:
- All tested ligands displayed similar pharmacological profiles across the three investigated responses.
- Reduction of ERK1/2 phosphorylation occurred with 40-500-fold higher potency compared to adenylyl cyclase stimulation or Ca2+ increase.
- A2B receptor activation in MBA-MD-231 cells leads to reduced ERK1/2 phosphorylation.
Conclusions:
- Selective activation of A2B adenosine receptors may allow targeting of cancer cell growth and proliferation.
- Exploiting the higher potency for ERK1/2 phosphorylation reduction could enable cancer therapy with fewer side effects.
- A2B receptor agonists could be developed to limit MAPK activity in cancers expressing these receptors without activating other pathways.
Related Concept Videos
01:28Insulin: The Receptor and Signaling Pathways
01:24Glucagon-like Receptor Agonists
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by...
01:25Drug-Receptor Interaction: Agonist
Agonists can bind to receptors in different ways. Some agonists bind directly to the receptor's active site, mimicking the endogenous...
01:19Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
03:14Notch Signaling Pathway
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not...
02:33Hedgehog Signaling Pathway