Abstract
The chemokine receptor 4 (CXCR4) and 7 (CXCR7) are G-protein-coupled receptors involved in various diseases including human cancer. As such, they have become important targets for therapeutic intervention. Cell-based receptor assays, able to detect agents that modulate receptor activity, are of key importance for drug discovery. We evaluated the potential of cellular electric impedance for this purpose. Dose-dependent and specific stimulation of CXCR4 was detected upon addition of its unique chemokine ligand CXCL12. The response magnitude correlated with the CXCR4 expression level. Gαi coupling and signaling contributed extensively to the impedance response, whereas Gαq- and Gβγ-related events had only minor effects on the impedance profile. CXCR7 signaling could not be detected using impedance measurements. However, increasing levels of CXCR7 expression significantly reduced the CXCR4-mediated impedance readout, suggesting a regulatory role for CXCR7 on CXCR4-mediated signaling. Taken together, cellular electric impedance spectroscopy can represent a valuable alternative pharmacological cell-based assay for the identification of molecules targeting CXCR4, but not for CXCR7 in the absence of CXCR4.
Highlights
G-protein-coupled receptors (GPCRs) are a large family of cell surface proteins that transduce a diverse array of extracellular stimuli into intracellular signals, and eventually, biological responses
CXC chemokine ligand 12 (CXCL12) induces a specific and dose-dependent cellular electric impedance response on CXC chemokine receptor 4 (CXCR4)-expressing cells while no such response is observed on CXCR7-expressing cells
A positive and transient CXCL12-induced Cell Index (CI) response was observed for U87.CD4.CXCR4
Summary
G-protein-coupled receptors (GPCRs) are a large family of cell surface proteins that transduce a diverse array of extracellular stimuli (e.g. peptide and protein hormones, biogenic amines, and lipids) into intracellular signals, and eventually, biological responses. GPCR activation is of key importance in many developmental and physiological processes, and as a consequence, aberrant GPCR signaling contributes to many human diseases [1]. This, in combination with the ability to modulate GPCRs pharmacologically, make GPCRs the most popular and validated drug target class in medicine [2]. The subfamily of chemokine receptors consists of about twenty GPCRs, most of which display canonical signaling via the activation of heterotrimeric G-proteins, some of them, referred to as atypical chemokine receptors, are devoid of G-protein-dependent signaling. The CXC chemokine receptor 4 (CXCR4) can only.
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