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Published on: February 21, 2020
Whole-cell biosensor for label-free detection of GPCR-mediated drug responses in personal cell lines
Julia M Hillger1, Jeffison Schoop1, Dorret I Boomsma2
1Division of Medicinal Chemistry, LACDR, Leiden University, The Netherlands.
Abstract:
Deciphering how genetic variation in drug targets such as G protein-coupled receptors (GPCRs) affects drug response is essential for precision medicine. GPCR signaling is traditionally investigated in artificial cell lines which do not provide sufficient physiological context. Patient-derived cell lines such as lymphoblastoid cell lines (LCLs) could represent the ideal cellular model system. Here we describe a novel label-free, whole-cell biosensor method for characterizing GPCR-mediated drug responses in LCLs. Generally, such biosensor technology is deemed only compatible with adherent cell lines. We optimized and applied the methodology to study cellular adhesion properties as well as GPCR drug responses in LCLs, which are suspension cells. Coating the detector surface with the extracellular matrix protein fibronectin resulted in cell adherence and allowed detection of cellular responses. A prototypical GPCR present on these cells, i.e. the cannabinoid receptor 2 (CB2), was selected for pharmacological characterization. Receptor activation with the agonist JWH133, blockade by antagonist AM630 as well as downstream signaling inhibition by PTX could be monitored sensitively and receptor-specifically. Potencies and effects were comparable between LCLs of two genetically unrelated individuals, providing the proof-of-principle that this biosensor technology can be applied to LCLs, despite their suspension cell nature, in order to serve as an in vitro model system for the evaluation of individual genetic influences on GPCR-mediated drug responses.
Insights
We developed a novel biosensor to measure drug responses in patient-derived cells, overcoming limitations of traditional cell models. This method enables personalized medicine by assessing genetic influences on G protein-coupled receptor (GPCR) drug effects.
Area of Science:
- Pharmacology
- Biotechnology
- Genetics
Background:
- Genetic variations in drug targets like G protein-coupled receptors (GPCRs) impact drug response, necessitating personalized medicine approaches.
- Traditional cell line models lack physiological relevance for studying GPCR signaling.
- Patient-derived lymphoblastoid cell lines (LCLs) offer a more accurate in vitro model system.
Purpose of the Study:
- To develop and validate a novel label-free, whole-cell biosensor for characterizing GPCR-mediated drug responses in LCLs.
- To adapt biosensor technology, typically for adherent cells, to suspension LCLs.
- To demonstrate the utility of this biosensor for evaluating individual genetic influences on drug response.
Main Methods:
- A label-free, whole-cell biosensor was optimized for suspension LCLs by coating detector surfaces with fibronectin to promote cell adherence.
- The biosensor was used to study cellular adhesion properties and G protein-coupled receptor (GPCR) drug responses.
- Pharmacological characterization of the cannabinoid receptor 2 (CB2) was performed using specific agonists and antagonists.
Main Results:
- The optimized biosensor successfully enabled GPCR drug response monitoring in suspension LCLs.
- Cellular responses, including receptor activation, blockade, and downstream signaling inhibition, were sensitively and specifically detected.
- Comparable results were obtained from LCLs of different individuals, proving the method's reliability.
Conclusions:
- This novel biosensor technology is applicable to suspension LCLs for studying GPCR-mediated drug responses.
- The method provides a valuable in vitro model for assessing individual genetic variations' impact on drug efficacy.
- This advancement supports the development of precision medicine strategies.
