Figure 1. Vesicular neurotransmitter transporters depend differentially on the chemical and electrical components of the H⁺ electrochemical gradient.

The vacuolar-type H⁺-ATPase generates the H⁺ electrochemical gradient (Δμ_H⁺) required for transport of all classical neurotransmitters into synaptic vesicles. However, different vesicular neurotransmitter transporters rely to differing extents on the two components of Δμ_H⁺, the chemical gradient (ΔpH) and the electrical gradient (Δψ). The vesicular accumulation of monoamines and ACh (left) involves the exchange of protonated cytosolic transmitter for two lumenal H⁺. The resulting movement of more H⁺ than charge dictates a greater dependence on ΔpH than Δψ for both VAChT and VMAT. Vesicular glutamate transport (right) may not involve H⁺ translocation. In the absence of Δψ, however, disruption of ΔpH inhibits uptake, suggesting that the transport of anionic glutamate involves exchange for nH⁺, resulting in the movement of n + 1 charge and hence greater dependence on Δψ than ΔpH. Transport of the neutral zwitterion GABA (and glycine) involves the movement of an equal number of H⁺ and charge, consistent with the similar dependence of VGAT on ΔpH and Δψ. These differences suggest that vesicles storing monoamines or ACh may have mechanisms to favor the accumulation of ΔpH at the expense of Δψ, whereas those storing glutamate may promote a larger Δψ. The extent to which vesicles differ in their expression of these two components remains unknown, but intracellular chloride carriers such as the synaptic vesicle-associated ClC-3 promote vesicle acidification by dissipating the positive Δψ developed by the vacuolar H⁺ pump, thereby disinhibiting the pump to make larger ΔpH. The VGLUTs can also contribute to formation of ΔpH because as an anion, glutamate entry similarly dissipates Δψ to promote ΔpH. Interestingly, a Cl⁻ conductance associated with the VGLUTs may also promote acidification by Cl⁻.