How to fill a vesicle

Nat. Neurosci., published online 28 August 2011, doi:10.1038/nn.2898

The filling of synaptic vesicles with neurotransmitters such as glutamate is regulated at multiple levels and most importantly by the H⁺ electrochemical driving force (Δμ_H+) that is generated by the vacuolar H⁺-translocating ATPase (V-ATPase). Δμ_H+ consists of a chemical gradient (ΔpH) and membrane potential (Δψ). When the anionic transmitter glutamate enters synaptic vesicles, it dissipates Δψ, enabling the H⁺-ATPase to create ΔpH. However, vesicular glutamate transport is itself driven by Δψ, and it has remained unclear whether Δψ might be regenerated from the accumulated ΔpH, enabling the vesicle to fill with greater amounts of the transmitter. From among the possible mechanisms to dissipate ΔpH, Goh et al. identified coupled cation (Na⁺)/H⁺ exchange activity that could reduce the ΔpH of synaptic vesicles but, because of the electroneutrality of the exchange, would maintain the Δψ produced by the V-ATPase activated by dissipation of ΔpH. Cations indeed stimulate either the uptake of glutamate into synaptic vesicles, an effect measured physiologically through an increase in quantal size, or the postsynaptic response to release of a single vesicle. Finally, the authors found that Na⁺/H⁺ exchangers (NHEs) mediate the stimulation of vesicular glutamate transport by cations. Overall, the results suggest that regulation of quantal size occurs via an increase in membrane potential mediated by K⁺/H⁺ exchange.