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Presynaptic regulation of quantal size: K+/H+ exchange stimulates vesicular glutamate transport

Nature Neuroscience volume 14, pages 1285–1292 (2011)Cite this article

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Abstract

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 (ΔμH+) generated by the vacuolar H+-ATPase drives the accumulation of classical transmitters into synaptic vesicles. The chemical component of ΔμH+ (ΔpH) 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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Figure 1: Synaptic vesicles express a Na+/H+ exchange activity.
Figure 2: Synaptic vesicles lack a detectable K+ channel conductance.
Figure 3: Cation/H+ exchange activity is present on glutamatergic synaptic vesicles and increases Δψ.
Figure 4: Monovalent cations increase glutamate transport into synaptic vesicles.
Figure 5: Cation/H+ exchange stimulates glutamate uptake by increasing Δψ.
Figure 6: Presynaptic K+ regulates mEPSC amplitude at the calyx of Held.
Figure 7: ΔpH-driven 22Na+ uptake into glutamatergic synaptic vesicles is sensitive to EIPA.

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  • 13 October 2011

    In the version of this article initially published online, the composition of the low-sodium and potassium-free NMDG patch clamp solution was omitted and a non-NMDG solution, not used in this work, was given instead. The error has been corrected in the PDF and HTML versions of this article

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Acknowledgements

We thank J. Orlowski, S. Schuldiner and members of the Edwards laboratory for many thoughtful discussions, S. Manandhar and F. Farrimond for technical assistance, and R.P. Seal for critical reading of the manuscript. This work was supported by fellowships from A*STAR (to G.Y.G.) and the American Heart Association (to L.B.), and by grants from the National Institute on Deafness and Other Communication Disorders and the National Institute of Neurological Disorders and Stroke (to L.O.T.), and from the National Institute of Mental Health and the National Institute on Drug Abuse (to R.H.E.).

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Author notes

  1. Hai Huang and Julie Ullman: These authors contributed equally to this work.

Authors and Affiliations

  1. Departments of Physiology and Neurology, Graduate Programs in Neuroscience, Cell Biology and Bioengineering, University of California, San Francisco, San Francisco, California, USA

    Germaine Y Goh, Julie Ullman, Lars Borre, Thomas S Hnasko & Robert H Edwards

  2. Oregon Hearing Research Center and Vollum Institute, Oregon Health and Science University, Portland, Oregon, USA

    Hai Huang & Laurence O Trussell

  3. Graduate Program in Molecular and Cellular Biology, University of California, Berkeley, Berkeley, California, USA

    Julie Ullman

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Contributions

The biochemical experiments were conducted by G.Y.G., J.U. and T.S.H. in the laboratory of R.H.E. L.B. developed the measurement of 22Na+ uptake. The electrophysiology experiments were performed by H.H. in the laboratory of L.O.T.

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Correspondence to Robert H Edwards.

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The authors declare no competing financial interests.

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Goh, G., Huang, H., Ullman, J. et al. Presynaptic regulation of quantal size: K+/H+ exchange stimulates vesicular glutamate transport. Nat Neurosci 14, 1285–1292 (2011). https://doi.org/10.1038/nn.2898

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