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Constitutive activity of the metabotropic glutamate receptor 2 explored with a whole-cell label-free biosensor

Overview of attention for article published in Biochemical Pharmacology, March 2018
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Title
Constitutive activity of the metabotropic glutamate receptor 2 explored with a whole-cell label-free biosensor
Published in
Biochemical Pharmacology, March 2018
DOI 10.1016/j.bcp.2018.03.026
Pubmed ID
Authors

Maarten L J Doornbos, Ilse Van der Linden, Liesbeth Vereyken, Gary Tresadern, Adriaan P IJzerman, Hilde Lavreysen, Laura H Heitman

Abstract

Label-free cellular assays using a biosensor provide new opportunities for studying G protein-coupled receptor (GPCR) signaling. As opposed to conventional in vitro assays, integrated receptor-mediated cellular responses are determined in real-time rather than a single downstream signaling pathway. In this study, we examined the potential of a label-free whole cell impedance-based biosensor system (i.e. xCELLigence) to study the pharmacology of one GPCR in particular, the mGlu2receptor. This receptor is a target for the treatment of several psychiatric diseases such as schizophrenia and depression. After optimization of assay conditions to prevent interference of endogenous glutamate in the culture medium, detailed pharmacological assessments were performed. Concentration-response curves showed a concentration-dependent increase in impedance for agonists and positive allosteric modulators, whereas receptor inhibition by an antagonist or negative allosteric modulator resulted in a concentration-dependent decrease in cellular impedance. Interestingly, constitutive receptor activity was observed that was decreased by LY341495, which therefore behaved as an inverse agonist here, a property that was heretofore unappreciated. This was confirmed by concentration-dependent modulation of LY341495 potency and efficacy by a allosteric modulators. In summary, the use of the xCELLigence system to study mGlu2receptor pharmacology was validated. This is the first class C GPCR to be characterized extensively by such method, opening new avenues to study receptor pharmacology including inverse agonism and demonstrating its value for future drug discovery efforts of mGlu receptors as well as other GPCRs.

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Mendeley readers

The data shown below were compiled from readership statistics for 41 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 41 100%

Demographic breakdown

Readers by professional status Count As %
Student > Master 7 17%
Researcher 5 12%
Student > Ph. D. Student 5 12%
Student > Doctoral Student 3 7%
Student > Bachelor 1 2%
Other 3 7%
Unknown 17 41%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 9 22%
Pharmacology, Toxicology and Pharmaceutical Science 5 12%
Agricultural and Biological Sciences 2 5%
Engineering 2 5%
Psychology 2 5%
Other 4 10%
Unknown 17 41%