A proline-rich motif on VGLUT1 reduces synaptic vesicle super-pool and spontaneous release frequency

Elife. 2019 Oct 30;8:e50401. doi: 10.7554/eLife.50401.


Glutamate secretion at excitatory synapses is tightly regulated to allow for the precise tuning of synaptic strength. Vesicular Glutamate Transporters (VGLUT) accumulate glutamate into synaptic vesicles (SV) and thereby regulate quantal size. Further, the number of release sites and the release probability of SVs maybe regulated by the organization of active-zone proteins and SV clusters. In the present work, we uncover a mechanism mediating an increased SV clustering through the interaction of VGLUT1 second proline-rich domain, endophilinA1 and intersectin1. This strengthening of SV clusters results in a combined reduction of axonal SV super-pool size and miniature excitatory events frequency. Our findings support a model in which clustered vesicles are held together through multiple weak interactions between Src homology three and proline-rich domains of synaptic proteins. In mammals, VGLUT1 gained a proline-rich sequence that recruits endophilinA1 and turns the transporter into a regulator of SV organization and spontaneous release.

Keywords: Vesicular Glutamate Transporter; axon; cell biology; liquid phase separation; mouse; neuroscience; neurotransmission; proline-rich domain; synaptic vesicle pools.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Biological Transport
  • Glutamates / metabolism*
  • Humans
  • Mice
  • Mice, Knockout
  • Rats
  • Synaptic Vesicles / metabolism*
  • Vesicular Glutamate Transport Protein 1 / deficiency
  • Vesicular Glutamate Transport Protein 1 / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Glutamates
  • SH3GL2 protein, human
  • Vesicular Glutamate Transport Protein 1