G protein βγ subunit-mediated presynaptic inhibition:: Regulation of exocytotic fusion downstream of Ca2+ entry

The nervous system can modulate neurotransmitter release by neurotransmitter activation of heterotrimeric GTP-binding protein (G protein)-coupled receptors. We found that microinjection of G protein beta gamma subunits (G beta gamma) mimics serotonin's inhibitory effect on neurotransmission. Release of free G beta gamma was critical for this effect because a G beta gamma scavenger blocked serotonin's effect. G beta gamma bad no effect on fast, action potential-evoked intracellular Ca2+ release that triggered neurotransmission. Inhibition of neurotransmitter release by serotonin was still seen after blockade of all classical G beta gamma effector pathways. Thus, G beta gamma blocked neurotransmitter release downstream of Ca2+ entry and may directly target the exocytotic fusion machinery at the presynaptic terminal.