期刊
BIOSENSORS & BIOELECTRONICS
卷 74, 期 -, 页码 233-242出版社
ELSEVIER ADVANCED TECHNOLOGY
DOI: 10.1016/j.bios.2015.06.031
关键词
G protein-coupled receptors, GPCR; Lymphoblastoid cell lines, LCL; Cannabinoid receptor 2, CB2; Label-free; Precision medicine; Personalized medicine
类别
资金
- Center for Collaborative Genomic Studies on Mental Disorders at the National Institute of Mental Health (NIMH) [NIMH U24 MH068457-06]
- Center for Collaborative Genomic Studies on Mental Disorders [NIMH U24 MH068457-06]
- Netherlands Twin Registry (NTR)
- Netherlands Twin Registry (NTR), part of the Center for Collaborative Genomic Studies on Mental Disorders [NIMH U24 MH068457-06]
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. (C) 2015 Elsevier B.V. All rights reserved.
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