Neuron
Volume 90, Issue 4, 18 May 2016, Pages 768-780
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Article
Protons Regulate Vesicular Glutamate Transporters through an Allosteric Mechanism

https://doi.org/10.1016/j.neuron.2016.03.026Get rights and content
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Highlights

  • VGLUTs exhibit an inwardly rectifying Cl conductance

  • Lumenal H+ and Cl allosterically activate Cl conductance and glutamate transport

  • VGLUT3 differs from other isoforms in pH dependence and glutamate transport

  • Requirement for external H+ limits glutamate efflux across the plasma membrane

Summary

The quantal nature of synaptic transmission requires a mechanism to transport neurotransmitter into synaptic vesicles without promoting non-vesicular efflux across the plasma membrane. Indeed, the vesicular transport of most classical transmitters involves a mechanism of H+ exchange, which restricts flux to acidic membranes such as synaptic vesicles. However, vesicular transport of the principal excitatory transmitter glutamate depends primarily on membrane potential, which would drive non-vesicular efflux, and the role of protons is unclear. Adapting electrophysiology to record currents associated with the vesicular glutamate transporters (VGLUTs), we characterize a chloride conductance that is gated by lumenal protons and chloride and supports glutamate uptake. Rather than coupling stoichiometrically to glutamate flux, lumenal protons and chloride allosterically activate vesicular glutamate transport. Gating by protons serves to inhibit what would otherwise be substantial non-vesicular glutamate efflux at the plasma membrane, thereby restricting VGLUT activity to synaptic vesicles.

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