title: Protons Regulate Vesicular Glutamate Transporters through an Allosteric Mechanism.
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.
authors.affiliation: Department of Physiology, UCSF School of Medicine, San Francisco, CA 94143, USA; Department of Neurology, UCSF School of Medicine, San Francisco, CA 94143, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Eriksen
authors.affiliation: 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.
authors.forename: Roger
authors.initials: R
authors.lastname: Chang
authors.affiliation: 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.
authors.forename: Matt
authors.initials: M
authors.lastname: McGregor
authors.affiliation: Department of Physiology, UCSF School of Medicine, San Francisco, CA 94143, USA; Department of Neurology, UCSF School of Medicine, San Francisco, CA 94143, USA.
authors.forename: Katlin
authors.initials: K
authors.lastname: Silm
authors.affiliation: Faculty of Science and Engineering, Waseda University, Shinjuku-ku, Tokyo 169-8555, Japan.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: 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.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Edwards
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D011522:Protons; D009435:Synaptic Transmission / Q000502:physiology*; D013572:Synaptic Vesicles / Q000378:metabolism*; D050496:Vesicular Glutamate Transport Proteins / Q000378:metabolism*
chemical_list: D018377:Neurotransmitter Agents; D011522:Protons; D050496:Vesicular Glutamate Transport Proteins; D018698:Glutamic Acid