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

G protein-coupled receptors (GPCRs) canonically couple to specific Gα protein subtypes and β-arrestin adaptor proteins to initiate cellular signaling events. G protein-mediated signaling and β-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 β-arrestins that are required for certain signaling and physiological events. Further adding to the intrigue of these newly appreciated G protein:β-arrestin complexes, only the Gαi subtype family members, and not Gαs, Gαq/11, or Gα12/13 subtypes, appear to form direct interactions with β-arrestin. Here, we review the recent discovery and initial characterization of G protein:β-arrestin complexes and describe how these complexes provide mechanistic insight into seemingly disparate observations. G protein:β-arrestin complexes build upon other observations of noncanonical G protein and β-arrestin signaling events to add an additional dimension to our understanding of GPCR signaling.