Of Chloride and Quantal Size

Abstract

The uptake into synaptic vesicles of glutamate—the major excitatory neurotransmitter in brain—depends on the proton electrochemical gradient generated by the vacuolar-type H + -ATPase and is modulated by extravesicular Cl – (see Schweizer). Extravesicular Cl – promotes the acidification of synaptic vesicles, a process that depends on its permeation into the vesicle, and Schenck et al . found that, whereas synaptic vesicles from mice lacking the CLC-3 Cl – channel acidified when exposed to ATP and Cl – , acidification was blunted in vesicles from mice lacking the major vesicular glutamate transporter (VGLUT1). Moreover, introduction of VGLUT1 into liposomes containing an electrogenic bacterial ATP synthase enabled their acidification by extravesicular Cl – . Thus, VGLUT1 itself mediates a major synaptic vesicle Cl – conductance. Like glutamate uptake into synaptic vesicles, glutamate uptake into VGLUT1-containing liposomes showed a biphasic dependence on external Cl – , with uptake greatest at low-mM external Cl – . Furthermore, experiments in which liposomes were preloaded with either 100 mM potassium chloride or 100 mM potassium gluconate revealed that luminal Cl – markedly enhanced ATP-dependent glutamate uptake. The promotion of glutamate uptake by luminal Cl – involved glutamate transport driven by the transmembrane electrical gradient (ΔΨ) generated by proton translocation; however, the transmembrane pH gradient contributed a component to glutamate uptake as well. Noting that the Cl – content of endocytosed synaptic vesicles depends on extracellular Cl – concentration, the authors propose that extracellular Cl – concentration may play a major role in regulating vesicular glutamate uptake and thus the size of individual quanta of neurotransmitter. S. Schenck, S. M. Wojcik, N. Brose, S. Takamori, A chloride conductance in VGLUT1 underlies maximal glutamate loading into synaptic vesicles. Nat. Neurosci. 12 , 156–162 (2009). [PubMed] F. E. Schweizer, Exit chloride, enter glutamate. Nat. Neurosci . 12 , 111–112 (2009). [PubMed]