G protein βγ directly regulates SNARE protein fusion machinery for secretory granule exocytosis

Abstract

The activation of G protein–coupled receptors (GPCRs) can result in an inhibition of Ca²⁺-dependent hormone and neurotransmitter secretion. This has been attributed in part to G protein inhibition of Ca²⁺ influx. However, a frequently dominant inhibitory effect, of unknown mechanism, also occurs distal to Ca²⁺ entry. Here we characterize direct inhibitory actions of G protein βγ (Gβγ) on Ca²⁺-triggered vesicle exocytosis in permeable PC12 cells. Gβγ inhibition was rapid (2+-dependent synaptotagmin binding. Here we show inhibitory coupling between GPCRs and vesicle exocytosis mediated directly by Gβγ interactions with the Ca²⁺-dependent fusion machinery.