Research ResourceGPCR SIGNALING

Functional selectivity profiling of the angiotensin II type 1 receptor using pathway-wide BRET signaling sensors

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Science Signaling  04 Dec 2018:
Vol. 11, Issue 559, eaat1631
DOI: 10.1126/scisignal.aat1631

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Biosensors for GPCR-biased signaling

Upon binding to ligands, G protein–coupled receptors (GPCRs) stimulate heterotrimeric G proteins and recruit β-arrestin, which dampens signaling through G proteins and acts as a scaffold to activate other pathways. Whereas some ligands stimulate both G proteins and β-arrestin, others preferentially stimulate one or the other, a phenomenon known as biased agonism. For receptors engaging more than one G protein subtype, ligands may also bias downstream signaling to a particular G protein. Namkung et al. developed bioluminescence resonance energy transfer (BRET) biosensors, which they used to characterize biased signaling downstream of the angiotensin II (AngII) type 1 receptor (AT1R) in response to various ligands, as well as the bias of naturally occurring AT1R variants. This tool kit can be used to comprehensively dissect the signaling bias of other GPCR-ligand combinations, which may benefit drug development efforts.