Non-canonical Golgi-compartmentalized G?? signaling: mechanisms, functions, and therapeutic targets

G protein G beta gamma subunits are key mediators of G protein-coupled receptor (GPCR) signaling under physiological and pathological conditions; their inhibitors have been tested for the treatment of human disease. Conventional wisdom is that the G beta gamma complex is activated and subsequently exerts its functions at the plasma mem-brane (PM). Recent studies have revealed non-canonical activation of G beta gamma at intra-cellular organelles, where the Golgi apparatus is a major locale, via translocation or local activation. Golgi-localized G beta gamma activates specific signaling cascades and reg-ulates fundamental cell processes such as membrane trafficking, proliferation, and migration. More recent studies have shown that inhibiting Golgi-compartmentalized G beta gamma signaling attenuates cardiomyocyte hypertrophy and prostate tumorigenesis, indicating new therapeutic targets. We review novel activation mechanisms and non-canonical functions of G beta gamma at the Golgi, and discuss potential therapeutic inter-ventions by targeting Golgi-biased G beta gamma-directed signaling.