The amount of neurotransmitter stored in a single synaptic vesicle can determine the size of the postsynaptic response, but the factors that regulate vesicle filling are poorly understood. A proton electrochemical gradient (δ μH+) generated by the vacuolar H +-ATPase drives the accumulation of classical transmitters into synaptic vesicles. The chemical component of δ μH+ (δH) has received particular attention for its role in the vesicular transport of cationic transmitters as well as in protein sorting and degradation. Thus, considerable work has addressed the factors that promote δpH. However, synaptic vesicle uptake of the principal excitatory transmitter glutamate depends on the electrical component of δμH+ (δψ). We found that rat brain synaptic vesicles express monovalent cation/H+ exchange activity that converts δpH into δψ, and that this promotes synaptic vesicle filling with glutamate. Manipulating presynaptic K+ at a glutamatergic synapse influenced quantal size, indicating that synaptic vesicle K+/H+ exchange regulates glutamate release and synaptic transmission.
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