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

G protein Gβγ 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 Gβγ complex is activated and subsequently exerts its functions at the plasma membrane (PM). Recent studies have revealed non-canonical activation of Gβγ at intracellular organelles, where the Golgi apparatus is a major locale, via translocation or local activation. Golgi-localized Gβγ activates specific signaling cascades and regulates fundamental cell processes such as membrane trafficking, proliferation, and migration. More recent studies have shown that inhibiting Golgi-compartmentalized Gβγ signaling attenuates cardiomyocyte hypertrophy and prostate tumorigenesis, indicating new therapeutic targets. We review novel activation mechanisms and non-canonical functions of Gβγ at the Golgi, and discuss potential therapeutic interventions by targeting Golgi-biased Gβγ-directed signaling.