Illuminating Gβ5 signaling

G proteins are key intermediates in cellular signaling and act in response to a variety of extracellular stimuli. The prevailing paradigm is that G protein subunits form a heterotrimeric complex and function principally at the plasma membrane. However, there is growing evidence for localization at, and signaling by, G proteins at intracellular compartments. Moreover, different cellular pools of G proteins may be composed of distinct subunit subtypes, including some binding partners that function in the place of G protein gamma subunits. An article in this issue of Molecular Pharmacology (Yost et al., p. 812) describes the use of an innovative fluorescent cell imaging technique to study interactions of the G protein beta(5) subunit with a panel of G gamma subunits as well as regulator of G protein signaling (RGS) proteins that contain a G gamma-like subdomain. The approach used here provides a new strategy to elucidate the spatial and temporal properties of G proteins, including a growing number of atypical G beta gamma pairings.