G Protein βγ Subunit-Mediated Presynaptic Inhibition: Regulation of Exocytotic Fusion Downstream of Ca 2+ Entry

Abstract

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 βγ subunits (Gβγ) mimics serotonin's inhibitory effect on neurotransmission. Release of free Gβγ was critical for this effect because a Gβγ scavenger blocked serotonin's effect. Gβγ had no effect on fast, action potential–evoked intracellular Ca ²⁺ release that triggered neurotransmission. Inhibition of neurotransmitter release by serotonin was still seen after blockade of all classical Gβγ effector pathways. Thus, Gβγ blocked neurotransmitter release downstream of Ca ²⁺ entry and may directly target the exocytotic fusion machinery at the presynaptic terminal.