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N-type Ca2+ channels carry the largest current: implications for nanodomains and transmitter release

Nature Neuroscience volume 13, pages 1348–1350 (2010)Cite this article

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Abstract

Presynaptic terminals favor intermediate-conductance CaV2.2 (N type) over high-conductance CaV1 (L type) channels for single-channel, Ca2+ nanodomain–triggered synaptic vesicle fusion. However, the standard CaV1>CaV2>CaV3 conductance hierarchy is based on recordings using nonphysiological divalent ion concentrations. We found that, with physiological Ca2+ gradients, the hierarchy was CaV2.2>CaV1>CaV3. Mathematical modeling predicts that the CaV2.2 Ca2+ nanodomain, which is ∼25% more extensive than that generated by CaV1, can activate a calcium-fusion sensor located on the proximal face of the synaptic vesicle.

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Figure 1: Single-channel currents and external calcium.
Figure 2: Comparison of CaV channel Ca2+ permeation.

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Acknowledgements

We thank G. Zamponi, P. Backx, S. Ikeda and A. Chan for critique of the manuscript, and Q. Li and X.P. Zhu for technical assistance. This work was supported primarily by Canadian Institutes for Health Research (MOP-86643) and a Canada Research Chair (E.F.S.). We also received funding from the Canadian Institutes for Health Research (MT-13657, L.C.S.), Ontario Graduate Scholarship (F.K.W.) and National Science Foundation (DMS-0817703, V.M.).

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Author notes

  1. Alexander M Weber and Fiona K Wong: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Synaptic Transmission, Toronto Western Research Institute, Toronto, Ontario, Canada

    Alexander M Weber, Fiona K Wong, Adele R Tufford & Elise F Stanley

  2. Genes and Development Division, Toronto Western Research Institute, Toronto, Ontario, Canada

    Alexander M Weber, Fiona K Wong, Adele R Tufford, Lyanne C Schlichter & Elise F Stanley

  3. Department of Mathematical Sciences, New Jersey Institute of Technology, Newark, New Jersey, USA

    Victor Matveev

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  1. Alexander M Weber
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Contributions

A.M.W., F.K.W. and A.R.T. collected data and critiqued the manuscript. L.C.S. contributed RT-PCR data and biophysical and editorial insight. V.M. carried out the mathematical simulations. E.F.S. conceived and directed the project, carried out the analysis and interpretation, and wrote the manuscript.

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Correspondence to Elise F Stanley.

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The authors declare no competing financial interests.

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Supplementary Figures 1–9, Supplementary Table 1, Supplementary Notes 1–4 and Supplementary Methods (PDF 1299 kb)

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Weber, A., Wong, F., Tufford, A. et al. N-type Ca2+ channels carry the largest current: implications for nanodomains and transmitter release. Nat Neurosci 13, 1348–1350 (2010). https://doi.org/10.1038/nn.2657

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