G protein betagamma 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 betagamma subunits (Gbetagamma) mimics serotonin's inhibitory effect on neurotransmission. Release of free Gbetagamma was critical for this effect because a Gbetagamma scavenger blocked serotonin's effect. Gbetagamma had 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 Gbetagamma effector pathways. Thus, Gbetagamma blocked neurotransmitter release downstream of Ca2+ entry and may directly target the exocytotic fusion machinery at the presynaptic terminal.
Blackmer
T
T
Department of Molecular Pharmacology and Biological Chemistry, Department of Physiology, Northwestern University Institute for Neuroscience, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611, USA.
Larsen
E C
EC
Takahashi
M
M
Martin
T F
TF
Alford
S
S
Hamm
H E
HE
D000200:Action Potentials; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D001369:Axons / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005089:Exocytosis; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D020962:Heterotrimeric GTP-Binding Proteins / Q000494:pharmacology*; D015640:Ion Channel Gating; D007798:Lampreys; D008565:Membrane Proteins / Q000378:metabolism; D008845:Microinjections; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009433:Neural Inhibition; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D050683:R-SNARE Proteins; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects*; D050825:Synaptosomal-Associated Protein 25; D050827:Syntaxin 1; D051552:beta-Adrenergic Receptor Kinases
D000954:Antigens, Surface; D015220:Calcium Channels; C118981:G-protein Beta gamma; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D050683:R-SNARE Proteins; D011993:Recombinant Fusion Proteins; D050825:Synaptosomal-Associated Protein 25; D050827:Syntaxin 1; D012701:Serotonin; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases; D020962:Heterotrimeric GTP-Binding Proteins; D002118:Calcium