A Biosensor Based, High-throughput Capable Cell Line for GPCR Ligand Analysis

Authors

• R Alvarez
• C Westover
• A Yazdin
• J Russ
• L Eiden
• A Emery
• W Xu
• M Eiden

Abstract

G Protein-Coupled Receptors (GPCRs) comprise a large receptor family characterized structurally by seven transmembrane domains and biochemically by its recruitment of G-proteins that initiate the cAMP pathway. Given their widespread distribution in numerous cells types soley in Eucaryotes, GPCRs are the targets of over 30% of drugs including antipsychotics, bronchodilators, antihypertensives, and drugs to treat Parkinson’s disease, and have been the focus of drug discovery in neuropharmacology and onco-, cardio-, broncho-, immune-, and gastrointestino- pharmacology. GPCRs act by sensing ligands outside the cell such as light sensitive compounds, odors, pheromones, hormones, and neurotransmitters. Upon ligand binding, GPCRs undergo a conformational change that enables GDP-GTP exchange on the associated G-protein, which catalyzes enzymatic formation of second messenger molecules, downstream cascades of signal transduction events, and ultimately to unique cellular responses. Previously, GPCR assays for testing drug responses and discovering downstream signaling molecules were primarily cumbersome biochemical or tissue-based ones. However, these methods fail to capture the complexity of GPCR signaling events such as screening for agents that can block, stimulate, or bias signaling to specific pathways that only in cellular assays can deliver. Cellular assays offer the possibility of high-throughput drug screening not only to identify agonists or antagonists for receptors with identified endogenous ligands, but also agonists for so-called orphan receptors, i.e. GPCRs with no identified endogenous agonist.

Scientific Focus Area: Molecular Pharmacology

This page was last updated on Friday, March 26, 2021