Gbetagamma acts at the C terminus of SNAP-25 to mediate presynaptic inhibition

Nat Neurosci. 2005 May;8(5):597-605. doi: 10.1038/nn1439. Epub 2005 Apr 17.


Presynaptic inhibition mediated by G protein-coupled receptors may involve a direct interaction between G proteins and the vesicle fusion machinery. The molecular target of this pathway is unknown. We demonstrate that Gbetagamma-mediated presynaptic inhibition in lamprey central synapses occurs downstream from voltage-gated Ca(2+) channels. Using presynaptic microinjections of botulinum toxins (BoNTs) during paired recordings, we find that cleavage of synaptobrevin in unprimed vesicles leads to an eventual exhaustion of synaptic transmission but does not prevent Gbetagamma-mediated inhibition. In contrast, cleavage of the C-terminal nine amino acids of the 25 kDa synaptosome-associated protein (SNAP-25) by BoNT A prevents Gbetagamma-mediated inhibition. Moreover, a peptide containing the region of SNAP-25 cleaved by BoNT A blocks the Gbetagamma inhibitory effect. Finally, removal of the last nine amino acids of the C-terminus of SNAP-25 weakens Gbetagamma interactions with soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes. Thus, the C terminus of SNAP-25, which links synaptotagmin I to the SNARE complex, may represent a target of Gbetagamma for presynaptic inhibition.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anterior Horn Cells / drug effects
  • Anterior Horn Cells / metabolism
  • Botulinum Toxins / pharmacology
  • Calcium Channels / metabolism
  • Calcium-Binding Proteins / metabolism
  • Efferent Pathways / drug effects
  • Efferent Pathways / metabolism
  • GTP-Binding Protein beta Subunits / metabolism*
  • GTP-Binding Protein gamma Subunits / metabolism*
  • Lampreys
  • Membrane Fusion / drug effects
  • Membrane Fusion / physiology*
  • Membrane Glycoproteins / metabolism
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism*
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / metabolism*
  • Neural Inhibition / drug effects
  • Neural Inhibition / physiology*
  • Neurotransmitter Agents / metabolism
  • Patch-Clamp Techniques
  • Photolysis
  • Presynaptic Terminals / drug effects
  • Presynaptic Terminals / metabolism*
  • Protein Structure, Tertiary / physiology
  • R-SNARE Proteins
  • SNARE Proteins
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology*
  • Synaptic Vesicles / drug effects
  • Synaptic Vesicles / metabolism*
  • Synaptosomal-Associated Protein 25
  • Synaptotagmin I
  • Synaptotagmins
  • Vesicular Transport Proteins / metabolism


  • Calcium Channels
  • Calcium-Binding Proteins
  • G-protein Beta gamma
  • GTP-Binding Protein beta Subunits
  • GTP-Binding Protein gamma Subunits
  • Membrane Glycoproteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Neurotransmitter Agents
  • R-SNARE Proteins
  • SNARE Proteins
  • Synaptosomal-Associated Protein 25
  • Synaptotagmin I
  • Vesicular Transport Proteins
  • Synaptotagmins
  • Botulinum Toxins