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Neuron. 2016 May 18;90(4):768-80. doi: 10.1016/j.neuron.2016.03.026. Epub 2016 Apr 28.

Protons Regulate Vesicular Glutamate Transporters through an Allosteric Mechanism.

Author information

1
Department of Physiology, UCSF School of Medicine, San Francisco, CA 94143, USA; Department of Neurology, UCSF School of Medicine, San Francisco, CA 94143, USA.
2
Department of Physiology, UCSF School of Medicine, San Francisco, CA 94143, USA; Department of Neurology, UCSF School of Medicine, San Francisco, CA 94143, USA; Graduate Program in Biomedical Sciences, UCSF School of Medicine, San Francisco, CA 94143, USA.
3
Department of Physiology, UCSF School of Medicine, San Francisco, CA 94143, USA; Department of Neurology, UCSF School of Medicine, San Francisco, CA 94143, USA; Graduate Program in Neuroscience, UCSF School of Medicine, San Francisco, CA 94143, USA.
4
Faculty of Science and Engineering, Waseda University, Shinjuku-ku, Tokyo 169-8555, Japan.
5
Department of Physiology, UCSF School of Medicine, San Francisco, CA 94143, USA; Department of Neurology, UCSF School of Medicine, San Francisco, CA 94143, USA; Graduate Program in Biomedical Sciences, UCSF School of Medicine, San Francisco, CA 94143, USA; Graduate Program in Neuroscience, UCSF School of Medicine, San Francisco, CA 94143, USA. Electronic address: robert.edwards@ucsf.edu.

Abstract

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.

PMID:
27133463
PMCID:
PMC4886649
DOI:
10.1016/j.neuron.2016.03.026
[Indexed for MEDLINE]
Free PMC Article

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