α-Neurexins couple Ca2+ channels to synaptic vesicle exocytosis

Abstract

Synapses are specialized intercellular junctions in which cell adhesion molecules connect the presynaptic machinery for neurotransmitter release to the postsynaptic machinery for receptor signalling. Neurotransmitter release requires the presynaptic co-assembly of Ca2+ channels with the secretory apparatus, but little is known about how synaptic components are organized. α-Neurexins, a family of >1,000 presynaptic cell-surface proteins encoded by three genes, link the pre- and postsynaptic compartments of synapses by binding extracellularly to postsynaptic cell adhesion molecules and intracellularly to presynaptic PDZ domain proteins. Using triple-knockout mice, we show that α-neurexins are not required for synapse formation, but are essential for Ca2+-triggered neurotransmitter release. Neurotransmitter release is impaired because synaptic Ca2+ channel function is markedly reduced, although the number of cell-surface Ca2+ channels appears normal. These data suggest that α-neurexins organize presynaptic terminals by functionally coupling Ca2+ channels to the presynaptic machinery.

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Figure 1: Essential role of α-neurexins.
Figure 2: Reduced spontaneous neurotransmitter release (minis) in the neocortex and brainstem from α-neurexin KO mice.
Figure 3: Impaired evoked neurotransmitter release in neocortical synapses from α-neurexin KO mice.
Figure 4: Evoked excitatory synaptic responses in brainstem synapses: effect of ω-conotoxin.
Figure 5: Impaired Ca2+ channel function in α-neurexin KO mice: rescue by transgenic neurexin 1α.
Figure 6: Ca2+ channels are normally expressed in α-neurexin KO mice but are partly inactivated after synaptic contacts are established.

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Acknowledgements

We thank A. Roth, I. Leznicki, E. Borowicz, K. Fricke, C. Bertram and S. Gerke for technical assistance; K. Nebendahl for help with mouse husbandry; D. Schild and M. Rickmann for use of confocal and electron microscopes; R. Jahn for antibodies; and J. Goldstein, M. S. Brown, E. Neher, P. Brehm, D. W. Richter and H. Hatt for advice. This study was supported by grants from the NIMH (to T.C.S.) and the Deutsche Forschungsgemeinschaft (to M.M., K.G. and W.Z.).

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Correspondence to Markus Missler or Thomas C. Südhof.

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Missler, M., Zhang, W., Rohlmann, A. et al. α-Neurexins couple Ca2+ channels to synaptic vesicle exocytosis. Nature 423, 939–948 (2003). https://doi.org/10.1038/nature01755

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