Noncanonical interactions of G proteins and β-arrestins: from competitors to companions

G protein-coupled receptors (GPCRs) canonically couple to specific G alpha protein subtypes and beta-arrestin adaptor proteins to initiate cellular signaling events. G protein-mediated signaling and beta-arrestin-mediated signaling have broadly been considered separable. However, noncanonical interactions between G proteins and GPCRs are now appreciated that do not result in nucleotide exchange and classical G protein signaling. New findings also demonstrate direct interactions between G proteins and beta-arrestins that are required for certain signaling and physiological events. Further adding to the intrigue of these newly appreciated G protein:beta-arrestin complexes, only the G alpha i subtype family members, and not G alpha s, G alpha q/11, or G alpha 12/13 subtypes, appear to form direct interactions with beta-arrestin. Here, we review the recent discovery and initial characterization of G protein:beta-arrestin complexes and describe how these complexes provide mechanistic insight into seemingly disparate observations. G protein:beta-arrestin complexes build upon other observations of noncanonical G protein and beta-arrestin signaling events to add an additional dimension to our understanding of GPCR signaling.

Automated summary

Recent discoveries have shown direct interactions between G proteins and beta-arrestins, essential for signaling and physiological events. Only members of the Gαi subtype family can form direct interactions with beta-arrestin, while other Gα subtypes do not possess this characteristic.