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The Journal of Neuroscience, January 28, 2009, 29(4):883-897; doi:10.1523/JNEUROSCI.4521-08.2009

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Cellular/Molecular
SV2 Renders Primed Synaptic Vesicles Competent for Ca²⁺-Induced Exocytosis

Wen-Pin Chang¹ and Thomas C. Südhof^1,2,3,4

Departments of ¹Neuroscience and ²Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9111, ³Neuroscience Institute and Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Palo Alto, California 94304-5543, and ⁴Howard Hughes Medical Institute at University of Texas Southwestern Medical Center and Stanford University School of Medicine

Correspondence should be addressed to Thomas C. Südhof at his present address: Neuroscience Institute, Department of Molecular and Cellular Physiology, and Howard Hughes Medical Institute, Stanford University School of Medicine, Palo Alto, CA 94304-5543. Email: tcs1{at}stanford.edu

Synaptic vesicle protein 2 (SV2), one of the first synaptic vesicle proteins identified, is characterized by multiple transmembrane regions that exhibit homology to sugar transporters, and by a highly glycosylated intravesicular sequence. Deletion of SV2 causes postnatal lethality in mice, primarily because of fulminant epilepsy. At the cellular level, deletion of SV2 impairs neurotransmitter release, but its function is unknown, and even the exact point at which release is affected in SV2-deleted synapses remains unclear. Using electrophysiological approaches, we now examine at what step in exocytosis the deletion of SV2 impairs release. Our data demonstrate that deletion of SV2 produces a decrease in evoked synaptic responses without causing changes in mini frequency, mini amplitude, the readily releasable pool of vesicles, or the apparent Ca²⁺ sensitivity of vesicle fusion. These findings indicate that a previously unidentified step may couple priming of synaptic vesicles to Ca²⁺ triggering of fusion, and that SV2 acts in this step to render primed synaptic vesicles fully Ca²⁺ responsive. To investigate the structural requirements for this function of SV2, we used rescue experiments. We demonstrate that conserved charged residues within the transmembrane regions and the intravesicular glycosylation of SV2 are required for its normal folding and trafficking. In contrast, the conserved putative synaptotagmin-binding sequence of SV2 is fully dispensable. Viewed together, these observations suggest that SV2 functions in a maturation step of primed vesicles that converts the vesicles into a Ca²⁺- and synaptotagmin-responsive state.

Key words: synaptic vesicle; membrane fusion; synaptotagmin; readily releasable pool; neurotransmitter release; short-term synaptic plasticity

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Received Sept. 21, 2008; revised Nov. 21, 2008; accepted Nov. 26, 2008.

Correspondence should be addressed to Thomas C. Südhof at his present address: Neuroscience Institute, Department of Molecular and Cellular Physiology, and Howard Hughes Medical Institute, Stanford University School of Medicine, Palo Alto, CA 94304-5543. Email: tcs1{at}stanford.edu

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