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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
Published on: February 20, 2018
Pairwise agonist scanning predicts cellular signaling responses to combinatorial stimuli
Manash S Chatterjee1, Jeremy E Purvis, Lawrence F Brass
1Institute for Medicine and Engineering, Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Nature Biotechnology
|June 22, 2010
Summary
Pairwise agonist scanning (PAS) uses neural networks to predict cellular responses to multiple stimuli. This method efficiently models complex signal integration, aiding patient-specific clinical status evaluation and cell biology research.
Area of Science:
- Cellular biology
- Systems biology
- Computational biology
Background:
- Predicting cellular responses to multiple stimuli is crucial for understanding cell biology and patient health.
- Studying signaling pathways in isolation fails to capture complex cross-talk and combinatorial effects of multiple agonists.
Purpose of the Study:
- To develop and validate a novel strategy, pairwise agonist scanning (PAS), for predicting cellular responses to complex combinations of stimuli.
- To apply PAS to human platelets to predict calcium signaling responses to various agonists and concentrations.
Main Methods:
- Developed a neural network model trained on cellular responses to individual and pairwise combinations of agonists.
- Applied PAS to human platelets stimulated with six agonists (ADP, convulxin, U46619, SFLLRN, AYPGKF, PGE(2)) at three concentrations.
- Validated the model's predictive accuracy for single, sequential, ternary, and complex combinations (4-6 agonists).
Main Results:
- The PAS model accurately predicted cellular responses to various agonist combinations (R = 0.88).
- The model successfully predicted responses to sequential agonist additions and ternary combinations.
- PAS demonstrated efficacy in distinguishing phenotypic responses among different platelet donors.
Conclusions:
- Pairwise agonist scanning provides an efficient approach for predicting complex signal integration in cellular systems.
- This method facilitates patient-specific disease milieu analysis by modeling multi-agonist interactions.
- PAS advances the understanding of cellular signaling complexity and its clinical relevance.
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