Ion transport and regulation in a synaptic vesicle glutamate transporter

Science. 2020 May 22;368(6493):893-897. doi: 10.1126/science.aba9202.

Abstract

Synaptic vesicles accumulate neurotransmitters, enabling the quantal release by exocytosis that underlies synaptic transmission. Specific neurotransmitter transporters are responsible for this activity and therefore are essential for brain function. The vesicular glutamate transporters (VGLUTs) concentrate the principal excitatory neurotransmitter glutamate into synaptic vesicles, driven by membrane potential. However, the mechanism by which they do so remains poorly understood owing to a lack of structural information. We report the cryo-electron microscopy structure of rat VGLUT2 at 3.8-angstrom resolution and propose structure-based mechanisms for substrate recognition and allosteric activation by low pH and chloride. A potential permeation pathway for chloride intersects with the glutamate binding site. These results demonstrate how the activity of VGLUTs can be coordinated with large shifts in proton and chloride concentrations during the synaptic vesicle cycle to ensure normal synaptic transmission.

Publication types

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

MeSH terms

  • Allosteric Regulation
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Chloride Channels / chemistry*
  • Chloride Channels / metabolism*
  • Chlorides / metabolism*
  • Cryoelectron Microscopy
  • Glutamic Acid / metabolism*
  • Hydrogen-Ion Concentration
  • Ion Transport
  • Membrane Potentials
  • Protein Domains
  • Rats
  • Synaptic Vesicles / metabolism*
  • Vesicular Glutamate Transport Protein 2 / chemistry*
  • Vesicular Glutamate Transport Protein 2 / metabolism*

Substances

  • Chloride Channels
  • Chlorides
  • Slc17a6 protein, rat
  • Vesicular Glutamate Transport Protein 2
  • Glutamic Acid