RT Journal Article
SR Electronic
T1 Novel Screening Assay for the Selective Detection of G-Protein-Coupled Receptor Heteromer Signaling
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 179
OP 188
DO 10.1124/jpet.112.198655
VO 344
IS 1
A1 Richard M. van Rijn
A1 Jessica H. Harvey
A1 Daniela I. Brissett
A1 Julia N. DeFriel
A1 Jennifer L. Whistler
YR 2013
UL http://jpet.aspetjournals.org/content/344/1/179.abstract
AB Drugs targeting G-protein-coupled receptors (GPCRs) make up more than 25% of all prescribed medicines. The ability of GPCRs to form heteromers with unique signaling properties suggests an entirely new and unexplored pool of drug targets. However, current in vitro assays are ill equipped to detect heteromer-selective compounds. We have successfully adapted an approach, using fusion proteins of GPCRs and chimeric G proteins, to create an in vitro screening assay (in human embryonic kidney cells) in which only activated heteromers are detectable. Here we show that this assay can demonstrate heteromer-selective G-protein bias as well as measure transinhibition. Using this assay, we reveal that the δ-opioid receptor agonist ADL5859, which is currently in clinical trials, has a 10-fold higher potency against δ-opioid receptor homomers than δ/μ-opioid receptor heteromers (pEC50 = 6.7 ± 0.1 versus 5.8 ± 0.2). The assay enables the screening of large compound libraries to identify heteromer-selective compounds that could then be used in vivo to determine the functional role of heteromers and develop potential therapeutic agents.