Biased Signaling through G Protein-coupled Receptors

It is well-established that G protein-coupled receptors (GPCRs) transduce signals into cells using G proteins as intermediary molecules. beta-Arrestins are molecules involved in regulating GPCRs; however, it has recently been reported that beta-arrestins can also mediate signaling through GPCRs. Signaling through G proteins or beta-arrestins can be activated selectively using specific agonists; of the latter, those that can selectively activate either G proteins or beta-arrestins are called biased agonists. The clinical use of biased agonists could potentially induce fewer side effects. However, partial agonists can also explain the mechanism of G protein-biased agonists; thus, appropriate assay systems must be considered. Endogenous agonists are known to bind to orthosteric and allosteric sites in the agonist binding site, and the allosteric site is associated with the activity of biased agonists. This current review presents a detailed discussion of biased agonists.

Automated summary

It is well-established that GPCRs transduce signals into cells using G proteins. β-arrestins can also mediate signaling through GPCRs. Selective activation of signaling through G proteins or β-arrestins can be achieved using biased agonists. Biased agonists show promise for clinical use with potentially fewer side effects. The mechanism of G protein-biased agonists may involve partial agonists and appropriate assay systems should be considered.