Affinage

SV2A

Synaptic vesicle glycoprotein 2A · UniProt Q7L0J3

Length
742 aa
Mass
82.7 kDa
Annotated
2026-06-10
100 papers in source corpus 39 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SV2A is a synaptic vesicle membrane glycoprotein with the 12-transmembrane topology and sequence homology of the major facilitator superfamily, originally identified as a putative vesicular transporter (PMID:1519064, PMID:1355409) and expressed ubiquitously at brain synapses (PMID:8083732). Functionally, SV2A is required for action potential-dependent neurotransmission—its genetic loss in mice produces fatal seizures with selectively impaired GABAergic transmission (PMID:10611374)—and it acts by maintaining a Ca2+-responsive pool of release-competent (primed) vesicles rather than by setting mini frequency/amplitude or apparent Ca2+ sensitivity (PMID:11483953, PMID:19176798). A central molecular function is the trafficking and stabilization of the Ca2+ sensor synaptotagmin 1: SV2A directly binds synaptotagmin through its cytoplasmic N-terminus in a calcium-inhibited, isoform-specific manner (PMID:8910372), and a tyrosine-based endocytosis motif (Y46) recruits clathrin adaptors AP2, EPS15, and amphiphysin 2/Bin1 to sort both SV2A and synaptotagmin 1 to vesicles (PMID:20410110), a sorting function it shares redundantly with stonin 2 (PMID:26015569). Through these activities SV2A also governs presynaptic Ca2+ levels (PMID:20620874) and sets slower vesicle recycling kinetics preferentially at inhibitory terminals where it is enriched (PMID:32615146). Its large fourth luminal domain, bearing a conserved N-linked glycan, serves as the neuronal protein receptor for botulinum neurotoxins A, D, E, and F and tetanus toxin, with toxin entry requiring both the SV2 peptide/glycan and coincident ganglioside binding (PMID:16543415, PMID:18815274, PMID:21124874, PMID:27294781). The same luminal architecture and an outward-open substrate-binding cavity form the binding site for the antiepileptic drugs levetiracetam and brivaracetam, as defined by knockout, mutagenesis, and cryo-EM of full-length SV2A (PMID:15210974, PMID:25692762, PMID:38637505). Disease-associated SV2A missense mutations (L174Q, R383Q) mislocalize the protein, reduce synaptotagmin 1 binding/levels, and impair GABAergic release, linking SV2A dysfunction to epileptogenesis (PMID:27265781, PMID:32341095).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1992 High

    Established the structural identity of SV2A as a 12-TM MFS-homologous protein, framing the long-standing hypothesis that it is a vesicular transporter.

    Evidence cDNA cloning, topology prediction, and heterologous expression in COS cells

    PMID:1355409 PMID:1519064

    Open questions at the time
    • Sequence homology did not demonstrate any transport substrate or activity
    • No functional assay of the predicted transport
  2. 1996 High

    Identified a direct, calcium-regulated, isoform-specific physical link between SV2A and the Ca2+ sensor synaptotagmin, suggesting SV2A couples to the fusion machinery.

    Evidence Cross-linking, co-IP, and recombinant affinity chromatography with domain mapping

    PMID:8910372

    Open questions at the time
    • Did not establish whether the interaction is required for release in vivo
    • Functional consequence of calcium-regulated dissociation untested at this stage
  3. 1999 High

    Demonstrated that SV2A is essential for action potential-dependent (especially GABAergic) neurotransmission, moving it from a structural curiosity to a release-controlling protein.

    Evidence SV2A knockout mouse with IPSC electrophysiology and EM of synapse ultrastructure

    PMID:10611374

    Open questions at the time
    • Did not pinpoint which step of the release cycle is impaired
    • Molecular basis of the GABAergic selectivity unresolved
  4. 2001 High

    Localized SV2A's function to maintenance of the readily releasable/primed vesicle pool for Ca2+-stimulated exocytosis, with effects on SNARE complex assembly.

    Evidence Capacitance exocytosis measurements in KO chromaffin cells and SDS-resistant SNARE complex analysis

    PMID:11483953

    Open questions at the time
    • Mechanism linking SV2A to SNARE complex stability not defined
    • Whether the defect is upstream or downstream of priming unclear at this point
  5. 2009 High

    Refined the functional defect to a step that renders primed vesicles Ca2+-responsive, and showed transmembrane residues and luminal glycosylation are needed for SV2A folding/trafficking while the putative synaptotagmin-binding sequence is dispensable for this function.

    Evidence Electrophysiology with systematic TM-domain and glycosylation rescue mutants in SV2-null neurons

    PMID:19176798

    Open questions at the time
    • Did not reconcile dispensability of the synaptotagmin-binding sequence with later synaptotagmin trafficking roles
    • Identity of any transported substrate still unknown
  6. 2010 High

    Defined SV2A's trafficking mechanism via a tyrosine-based endocytosis motif recruiting clathrin adaptors and its role in synaptotagmin expression/trafficking, separating distinct functional modules.

    Evidence Y46A mutagenesis, adaptor binding assays, electrophysiology, and KO vesicle immunoisolation; additional TM tryptophan mutant analysis

    PMID:20410110 PMID:20702688

    Open questions at the time
    • Mechanistic separation of synaptotagmin regulation versus release support incompletely defined
    • How TM tryptophans support release independently of synaptotagmin unresolved
  7. 2010 High

    Showed SV2 acts through presynaptic Ca2+ regulation, with elevated resting/evoked Ca2+ causally responsible for altered vesicle dynamics in SV2-null terminals.

    Evidence Direct presynaptic Ca2+ imaging in SV2B-KO retinal bipolar terminals with pharmacological reproduction and rescue

    PMID:20620874

    Open questions at the time
    • Molecular target through which SV2 controls presynaptic Ca2+ not identified
    • Generality across SV2A-dominated synapses not tested here
  8. 2015 High

    Established that SV2A/B and stonin 2 act redundantly in endocytic sorting of synaptotagmin 1 to synaptic vesicles, explaining synaptotagmin loss and missorting upon SV2 deletion.

    Evidence Double genetic deletion epistasis with surface labeling and electrophysiology

    PMID:26015569

    Open questions at the time
    • Precise biochemical step at which SV2A and stonin 2 converge unresolved
    • Quantitative contribution of each pathway not separated
  9. 2006 High

    Identified SV2 as the neuronal protein receptor for botulinum neurotoxin A, defining a non-synaptic-vesicle function exploited by toxins.

    Evidence SV2A/B KO neurons, isoform rescue, fragment competition, and siRNA knockdown

    PMID:16543415

    Open questions at the time
    • Did not resolve the structural determinants of toxin recognition
    • Relative contributions of peptide versus glycan undefined at this stage
  10. 2016 High

    Provided the structural basis for toxin recognition, showing BoNT/A requires both the SV2 luminal-domain peptide and its conserved N-linked glycan, and quantified isoform/pH-dependent affinity.

    Evidence 2.0-Å crystal structure of BoNT/A1 RBD with glycosylated SV2C plus SPR/CD biophysics and glycosylation mutagenesis

    PMID:18815274 PMID:19476346 PMID:19650874 PMID:21124874 PMID:21483489 PMID:23621114 PMID:27196927 PMID:27294781

    Open questions at the time
    • Structures were of toxin-binding fragments rather than full-length SV2A in early studies
    • Endogenous vesicular function of the luminal domain distinct from toxin binding not addressed
  11. 2023 High

    Showed BoNT/A endocytosis requires coincident binding to polysialoganglioside and SV2 and exploits a preassembled ganglioside–synaptotagmin-1 complex to drive Syt1-SV2 nanoclustering for endocytic sorting.

    Evidence Live-cell super-resolution imaging, EM, receptor-binding mutants, Syt1 CRISPRi, and SNAP-25 cleavage assays

    PMID:37226896

    Open questions at the time
    • Stoichiometry of the multi-receptor assembly not fully defined
    • Whether nanoclustering reflects a physiological sorting mechanism beyond toxin entry untested
  12. 2014 Medium

    Provided the first direct evidence of a transport substrate, showing human SV2A confers galactose uptake in transport-deficient yeast and that levetiracetam inhibits this activity.

    Evidence Heterologous expression in hexose-transport-deficient yeast with direct galactose uptake measurement and LEV inhibition

    PMID:25326386

    Open questions at the time
    • Galactose transport not demonstrated in native neurons
    • Physiological relevance of galactose as a vesicular substrate unestablished
  13. 2024 High

    Resolved the structural basis of antiepileptic drug binding, showing levetiracetam and brivaracetam occupy the outward-open substrate cavity of full-length SV2A and explaining brivaracetam's higher affinity.

    Evidence Cryo-EM of full-length SV2A with BoNT/A2 RBD and LEV or BRV, plus spectral-shift binding affinity; supported by earlier D670 mutagenesis and LEV-binding-site studies

    PMID:15210974 PMID:22220214 PMID:23530581 PMID:25692762 PMID:38637505

    Open questions at the time
    • Conformational cycle linking drug occupancy to transport/synaptic function not captured
    • How drug binding modulates the physiological vesicle-priming role mechanistically unresolved
  14. 2020 High

    Connected SV2A dysfunction to epilepsy and broader disease, with human/rat missense mutations causing mislocalization and reduced synaptotagmin 1 binding, and SV2A loss contributing to C9orf72 ALS/FTD synaptic deficits.

    Evidence Disease-mutation knock-in/replacement models with imaging, FRAP, binding and trafficking assays, plus GA-dipeptide disease models with SV2A rescue

    PMID:27265781 PMID:32341095 PMID:32347002

    Open questions at the time
    • Whether mislocalization phenotypes generalize across all epilepsy-associated variants unknown
    • Mechanism linking SV2A loss to C9orf72 pathology not fully defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • The endogenous transport substrate, transport cycle, and how transporter conformational states couple to vesicle priming and drug action in native neurons remain unresolved.
  • No demonstrated physiological transport activity in neurons
  • Coupling of MFS conformational cycle to Ca2+-responsive priming undefined
  • Mechanistic basis of GABAergic/inhibitory-synapse selectivity incompletely explained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0001618 virus receptor activity 5 GO:0098772 molecular function regulator activity 4 GO:0005215 transporter activity 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0031410 cytoplasmic vesicle 4 GO:0005886 plasma membrane 3
Pathway
R-HSA-112316 Neuronal System 4 R-HSA-1643685 Disease 3 R-HSA-5653656 Vesicle-mediated transport 3
Partners
AP2BIN1EPS15LAMA5STON2SYT1

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 SV2A (SV2) is a 12-transmembrane-domain protein with sequence homology to the major facilitator superfamily (MFS) of bacterial transporters, specifically the N-terminal half showing identity to sugar/citrate/drug transporters and the C-terminal half to plasma membrane neurotransmitter transporters, suggesting a transporter function for synaptic vesicles. cDNA cloning, sequence analysis, topology prediction, and heterologous expression in COS cells Science High 1355409 1519064
1993 SV2 is a keratan sulfate proteoglycan on synaptic vesicles, existing in two electrophoretic forms (L form ~100 kDa and H form ~250 kDa), both containing the SV2 epitope on the cytoplasmic side of the vesicle membrane. Biochemical fractionation of synaptic vesicles, SDS-PAGE, immunoblotting, proteoglycan characterization Journal of neurochemistry Medium 7685814
1994 SV2A is expressed ubiquitously throughout the brain at all synapses, and immunoprecipitation of brain synaptic vesicles with isoform-specific antibodies showed that both SV2A and SV2B isoforms can be present on the same synaptic vesicle. In situ hybridization, immunohistochemistry, isoform-specific immunoprecipitation followed by Western blot The Journal of neuroscience High 8083732
1996 SV2A directly binds synaptotagmin in a calcium-regulated, isoform-specific manner: SV2A (but not SV2B) interacts with the C2B domain of synaptotagmin via SV2A's cytoplasmic amino terminus, and this interaction is inhibited by calcium with an EC50 of ~10 µM. Cross-linking, co-immunoprecipitation, recombinant protein affinity chromatography The Journal of biological chemistry High 8910372
1999 SV2A is essential for action potential-dependent GABAergic neurotransmission: SV2A knockout mice develop severe seizures and die within 3 weeks; electrophysiology of CA3 hippocampal neurons showed reduced action potential-dependent (but normal action potential-independent) GABAergic transmission, without changes in synapse density or morphology. Targeted gene disruption (knockout mouse), electrophysiology of spontaneous IPSCs, electron microscopy of synapse ultrastructure Proceedings of the National Academy of Sciences of the United States of America High 10611374
2001 SV2A is required to maintain the readily releasable pool (RRP) of vesicles for calcium-stimulated exocytosis: direct capacitance measurements in SV2A-knockout adrenal chromaffin cells showed a significantly reduced calcium-induced exocytotic burst (defining the RRP) with normal burst kinetics, and brain tissue from SV2A knockouts had fewer SDS-resistant SNARE complexes. Capacitance measurements (direct exocytosis assay) in chromaffin cells, SDS-resistant SNARE complex analysis by Western blot Nature cell biology High 11483953
2004 SV2A is the brain binding site for the antiepileptic drug levetiracetam: the LEV-binding site is enriched in synaptic vesicles (~90 kDa by photoaffinity labeling); brain membranes and vesicles from SV2A-knockout mice show no LEV-derivative binding; SV2A expressed in fibroblasts is sufficient for LEV binding; no binding occurs to SV2B or SV2C; binding affinity to SV2A correlates with seizure protection. Radioligand binding assays, photoaffinity labeling of purified synaptic vesicles, SV2A knockout mice, heterologous expression in fibroblasts Proceedings of the National Academy of Sciences of the United States of America High 15210974
2005 All three SV2 isoforms (SV2A, SV2B, SV2C) bind synaptotagmin via a common calcium-inhibited site; additionally, SV2A and SV2C (but not SV2B) possess a second N-terminal synaptotagmin-binding site that is calcium-stimulated; the N-terminal 57 amino acids of SV2A mediate this additional interaction; introduction of the SV2A or SV2C amino terminus into superior cervical ganglion neurons inhibited neurotransmission, whereas SV2B amino terminus did not. Co-immunoprecipitation of native SV2 isoforms, recombinant protein binding assays, domain mapping, microinjection of N-terminal peptides into neurons with electrophysiological readout Molecular and cellular neurosciences High 15866046
2006 SV2 (isoforms A, B, and C) is the protein receptor for botulinum neurotoxin A (BoNT/A): BoNT/A binding to neurons is abolished in SV2A/SV2B double-knockout hippocampal neurons and rescued by expressing any SV2 isoform; SV2 fragments containing the toxin interaction domain inhibit BoNT/A neuronal binding; reduction of SV2 in PC12 and Neuro-2a cells inhibits BoNT/A entry. SV2A/B knockout neurons, viral rescue experiments, SV2 fragment competition assay, siRNA knockdown in cell lines Science High 16543415
2008 SV2A adopts two major in situ conformations visualized by Protein Tomography: a compact funnel-structure with a pore-like opening toward the cytoplasm and a more open V-shaped structure with a cleft opening toward the intravesicular space, consistent with a transporter valve-like mechanism; levetiracetam binding does not cause a large-scale conformational change or lock a specific state. Protein Tomography (electron microscopy-based) of mouse brain tissue, comparison of LEV-treated vs. saline-treated samples Biochemical and biophysical research communications Medium 18692481
2008 N-glycosylation of SV2A is required for BoNT/E entry into neurons: a point mutation disrupting an N-glycosylation site in the fourth luminal domain of SV2A (N573Q) abolishes BoNT/E entry and reduces BoNT/A entry; glycosylated SV2A/SV2B (but not SV2C) serve as protein receptors for BoNT/E; gangliosides are also essential for BoNT/E binding. SV2A/B knockout neurons, viral rescue with wild-type or N573Q mutant SV2A, chimeric receptor strategy, exogenous ganglioside rescue Molecular biology of the cell High 18815274
2009 SV2 deletion impairs a step that renders primed vesicles Ca2+-responsive, rather than affecting mini frequency, mini amplitude, RRP size, or apparent Ca2+ sensitivity of fusion; conserved charged residues in transmembrane regions and intravesicular glycosylation are required for normal SV2A folding/trafficking; the putative synaptotagmin-binding sequence of SV2 is dispensable for this function. Electrophysiology in SV2-deleted hippocampal neurons, rescue experiments with transmembrane domain and glycosylation mutants The Journal of neuroscience High 19176798
2009 BoNT/F uses all three SV2 isoforms (SV2A, SV2B, SV2C) as protein receptors, as demonstrated by co-precipitation of SV2A, B, and C from Triton-solubilized synaptic vesicles by BoNT/F, competition with recombinant binding fragments, and activity in the phrenic nerve hemidiaphragm assay; gangliosides are also required. Co-precipitation from solubilized synaptic vesicles, phrenic nerve hemidiaphragm assay, site-directed mutagenesis of ganglioside-binding site, cross-competition assays Journal of neurochemistry High 19650874
2009 BoNT/F binds synaptic vesicle glycoproteins through the keratan sulfate moiety of SV2; crystal structure of HCR/F reveals two regions implicated in neuronal binding distinct from BoNT/A; HCR/F binds gangliosides containing α2,3-linked sialic acid (GD1a ≥ GT1b); mutations in the ganglioside binding pocket reduce binding to both gangliosides and SV2. X-ray crystallography of receptor-binding domain, solid phase glycan array, affinity chromatography, deglycosylation experiments, site-directed mutagenesis Biochemistry High 19476346
2010 SV2 mediates entry of tetanus neurotoxin into central neurons: toxin entry is dependent on synaptic vesicle recycling; tetanus neurotoxin cannot cleave its substrate synaptobrevin II in SV2-knockout neurons; entry is rescued by SV2A or SV2B expression; SV2A is preferentially localized to inhibitory terminals while SV2B is more localized to excitatory terminals in cortex. SV2 knockout neurons, viral rescue with SV2A or SV2B, synaptobrevin II cleavage assay, immunofluorescence co-localization PLoS pathogens High 21124874
2010 SV2 regulates synaptic transmission via a tyrosine-based endocytosis motif (Y46 in SV2A's cytoplasmic N-terminus) that is required for trafficking to synaptic vesicles: SV2A-Y46A mutant shows increased plasma membrane localization, fails to rescue neurotransmission, and binds clathrin adaptors AP2, EPS15, and amphiphysin 2/Bin1; SV2 also regulates synaptotagmin expression and trafficking (via a separate mechanism), and SV2A/B double-knockout vesicles contain less synaptotagmin. Site-directed mutagenesis (Y46A), electrophysiology in SV2-null neurons, in vitro binding assays for adaptor proteins, immunoisolation of synaptic vesicles from SV2A/B double KO mice The Journal of neuroscience High 20410110
2010 SV2 acts via presynaptic calcium regulation: loss of SV2B in retinal bipolar neurons elevates both resting and evoked presynaptic Ca2+ signals; this Ca2+ elevation is causally responsible for the altered synaptic vesicle dynamics, plasticity, and strength observed in SV2B-null synapses, as demonstrated by short-term reproduction of the Ca2+ phenotype in wild-type terminals and rescue of the Ca2+ phenotype in SV2B-null neurons. Direct presynaptic Ca2+ measurement (calcium imaging) in SV2B-knockout retinal bipolar terminals, pharmacological manipulation to reproduce/rescue Ca2+ phenotype Neuron High 20620874
2010 SV2A performs at least two mechanistically distinct functions: (1) regulating synaptotagmin expression and trafficking (dependent on the N-terminal endocytosis motif), and (2) supporting neurotransmitter release via conserved tryptophans in the 5th (W300) and 10th (W666) transmembrane domains, which are required for rescuing synaptic depression independently of synaptotagmin regulation. Site-directed mutagenesis of SV2A (R231Q, W300A, W666A), electrophysiology (synaptic depression assay) in SV2A/B double KO neurons, synaptotagmin expression and trafficking measurements American journal of physiology. Cell physiology High 20702688
2011 BoNT/D uses SV2 (all three isoforms, SV2A/B/C) as its protein receptor, entering neurons via synaptic vesicle recycling: BoNT/D binds SV2 in brain detergent extracts, fails to enter SV2-null neurons, is rescued by any SV2 isoform, and plasma membrane-localized SV2 is sufficient for BoNT/D binding in HEK293 cells; BoNT/D binds SV2 via a mechanism distinct from BoNT/A and BoNT/E. SV2-knockout neurons, viral rescue with SV2A/B/C, co-immunoprecipitation from brain detergent extracts, HEK293 cell binding assay PLoS pathogens High 21483489
2011 Levetiracetam binding to SV2A reverses the synaptic effects of SV2A overexpression: excess SV2A (~1.5-fold increase) reduces synaptic release probability and increases synaptotagmin levels at synapses; LEV treatment restores normal neurotransmission and normalizes SV2A and synaptotagmin levels. SV2A-EGFP overexpression in autaptic hippocampal neurons, electrophysiology, immunostaining, levetiracetam treatment PloS one Medium 22220214
2012 N-glycans on SV2A are only partially dispensable for synaptic localization and function, in contrast to synaptophysin where N-glycosylation is essential; glycosylation is completely dispensable for synaptotagmin 1 sorting to SVs. Mutagenesis of all N-glycosylation sites on SV2A, pHluorin-tagged proteins in cultured neurons from KO mice, optical imaging The Journal of biological chemistry Medium 22908222
2013 The SV2-binding interface of BoNT/E was identified: mutations at a site corresponding to the synaptotagmin-binding site of BoNT/B and at an extended surface area near the ganglioside-binding site impair SV2 binding, reduce neurotoxicity in the phrenic nerve hemidiaphragm assay, and a neutralizing antibody blocks BoNT/E by directly interfering with the BoNT/E-SV2 interaction. Site-directed mutagenesis of BoNT/E binding domain, binding assays, phrenic nerve hemidiaphragm functional assay, antibody neutralization assay The Biochemical journal High 23621114
2013 SV2A can be modulated allosterically: the compound UCB1244283 acts as a positive allosteric modulator of the [3H]UCB30889 binding site on SV2A, increasing affinity 5-fold and total binding sites 2-fold on both recombinant human SV2A and rat cortex, and slowing association/dissociation kinetics; this allosteric modulation also confers in vivo anticonvulsant protection. Saturation binding and kinetic radioligand binding assays on recombinant SV2A (HEK cells) and rat cortex, in vivo audiogenic seizure mouse model British journal of pharmacology Medium 23530581
2014 SV2A functions as a galactose transporter: human SV2A expressed in hexose transport-deficient yeast (EBY.VW4000) enables growth on galactose but not other carbon sources; direct galactose uptake measurements confirm transport; levetiracetam inhibits galactose-dependent growth of these cells. Heterologous expression in transport-deficient yeast, growth assays on different carbon sources, direct galactose uptake measurement, pharmacological inhibition by LEV The Journal of biological chemistry Medium 25326386
2015 Residue D670 of SV2A is critical for levetiracetam analogue binding: mutation of D670 leads to complete loss of radioligand binding, as predicted by homology modelling and molecular dynamics simulations of inward- and outward-facing MFS conformational states. Homology modelling, molecular dynamics, docking, site-directed mutagenesis, radioligand binding assay PloS one Medium 25692762
2015 SV2A/B and stonin 2 have overlapping functions in endocytic sorting of synaptotagmin 1 (Syt1) to synaptic vesicles: deletion or knockdown of either SV2A/B or stonin 2 causes partial Syt1 loss and missorting to the neuronal surface; deletion of both dramatically exacerbates Syt1 missorting and degradation, impairing neurotransmission efficacy. Genetic deletion of SV2A/B and stonin 2, knockdown, Syt1 immunostaining/surface labeling, electrophysiology in hippocampal synapses Proceedings of the National Academy of Sciences of the United States of America High 26015569
2016 N-linked glycosylation of SV2C (conserved across all SV2 isoforms and vertebrate species) is essential for BoNT/A1 binding to neurons and for potent neurotoxicity: the 2.0-Å crystal structure of BoNT/A1 receptor-binding domain in complex with glycosylated human SV2C reveals that neuronal tropism requires recognition of both the SV2C peptide moiety and an N-linked glycan on SV2. X-ray crystallography (2.0 Å resolution) of BoNT/A1 receptor-binding domain:glycosylated human SV2C complex, mutagenesis of glycosylation site, neuronal binding and toxicity assays Nature structural & molecular biology High 27294781
2016 BoNT/A binds SV2C-LD4 with a binding constant of ~200 nM; binding affinity decreases from SV2C >> SV2A > SV2B; at pH 5 (acidic synaptic vesicles), binding affinity increases >10-fold; the SV2C luminal domain 4 forms a quadrilateral β-sheet helix that pre-exists in solution prior to BoNT/A binding, constituting a different binding mechanism from BoNT/B-synaptotagmin. GST pull-down assays, surface plasmon resonance, circular dichroism spectroscopy, pH-dependent binding assays Toxins Medium 27196927
2016 SV2A dysfunction due to missense mutation L174Q selectively reduces depolarization-induced GABA (but not glutamate) release in the hippocampus and specifically reduces synaptotagmin 1 levels among exocytosis-related proteins, facilitating kindling epileptogenesis. Rat Sv2a L174Q missense knock-in model, neurochemical measurements of GABA/glutamate release, Western blot for exocytosis proteins, amygdala kindling assay Scientific reports High 27265781
2020 SV2A coordinates distinct synaptic vesicle recycling properties between inhibitory and excitatory nerve terminals: SV2A is more highly expressed in inhibitory synapses and its preferential presence controls slower vesicle recycling in inhibitory terminals (~1.8-fold slower than excitatory) by differentially regulating sorting of synaptotagmin I. pHluorin-conjugated SV2 tracers preferentially expressed in excitatory or inhibitory terminals, fluorescence imaging of vesicle recycling kinetics, comparison across terminal types Progress in neurobiology Medium 32615146
2020 The epilepsy-associated human SV2A mutation R383Q causes mislocalization of SV2A from synaptic vesicles to the plasma membrane, reduces mobility at the plasma membrane, reduces binding to synaptotagmin-1 (Syt1), and fails to rescue reduced Syt1 expression and dysfunctional activity-dependent Syt1 trafficking in SV2A-depleted neurons. Molecular replacement strategy in SV2A-depleted mouse neurons, live-cell imaging of plasma membrane vs. vesicular localization, FRAP, co-immunoprecipitation for Syt1 binding, Syt1 trafficking assays The Journal of neuroscience High 32341095
2020 Poly-glycine-alanine (GA) dipeptide aggregates from C9orf72 ALS/FTD reduce SV2A levels in motor neurons, alter Ca2+ influx, and impair synaptic vesicle release; restoring SV2A levels rescues these synaptic phenotypes. GA mouse model and patient iPSC-derived neurons, SV2A protein quantification, Ca2+ imaging, synaptic vesicle release assays, SV2A rescue experiments EMBO molecular medicine Medium 32347002
2023 BoNT/A endocytosis into synaptic vesicles requires coincident binding to both polysialoganglioside (PSG) and SV2 on the neuronal plasma membrane; BoNT/A simultaneously interacts with a preassembled PSG-synaptotagmin-1 (Syt1) complex and SV2, facilitating Syt1-SV2 nanoclustering that controls endocytic sorting into SVs; Syt1 knockdown suppresses BoNT/A and BoNT/E intoxication. Live-cell super-resolution imaging, electron microscopy, catalytically inactivated BoNT/A and receptor-binding-deficient mutants in hippocampal neurons, Syt1 CRISPRi knockdown, SNAP-25 cleavage assay The EMBO journal High 37226896
2024 Cryo-EM structures of full-length SV2A in complex with BoNT/A2 receptor-binding domain and either levetiracetam or brivaracetam reveal: (1) the large fourth luminal domain of SV2A binds BoNT/A2 HC through protein-protein and protein-glycan interactions; (2) LEV and BRV occupy the putative substrate-binding site in an outward-open conformation; (3) a propyl group in BRV creates additional contacts with SV2A explaining its higher binding affinity than LEV. Cryo-electron microscopy of full-length SV2A complexes, label-free spectral shift assay for binding affinity Nature communications High 38637505
1996 SV2 is localized on the membranes of both synaptic vesicle clusters and large dense-cored vesicles (LDCV) in NGF-treated PC12 cells, with a higher SV2:synaptophysin ratio on LDCV (~9:1) compared to synaptic vesicle clusters (~1:1); chromogranin A occupies the LDCV core while SV2 is on the membrane. Pre-embedding EM immunocytochemistry with silver-enhanced gold probe, quantitative comparison on identified organelle types The journal of histochemistry and cytochemistry Medium 8985140
2000 SV2 (synaptic vesicle transmembrane proteoglycan) is complexed with an α5-chain-containing laminin on the presynaptic plasma membrane: SV2 co-purifies with a 900-kDa laminin from synaptosomes of electric organ synapses, and purified SV2 binds laminin-1 with high affinity in direct binding assays. Synaptosome preparation, co-immunoprecipitation/co-purification of SV2-laminin complex, direct binding assay with purified SV2 and laminin-1 The Journal of biological chemistry Medium 10617638
2020 SV2A is expressed in mitochondria (in addition to synaptic vesicles), as demonstrated by immunohistochemistry and proteomics; levetiracetam effects on mitochondrial function (fission/fusion balance, permeability transition pore) are significantly abolished when SV2A is knocked down by siRNA. Immunohistochemistry, proteomics, siRNA knockdown of SV2A, mitochondrial functional assays (fission/fusion, mPTP opening) Journal of Alzheimer's disease Low 26639968
2020 miR-133a and miR-218 directly target SV2A: luciferase reporter assay showed these miRNAs significantly decreased relative luciferase activity from an SV2A dual-luciferase construct; transfection of miR-133a and miR-218 in human neuroblastoma cells reduced endogenous SV2A mRNA and protein levels. Luciferase reporter assay, miRNA transfection in human neuroblastoma cells, qRT-PCR, Western blot Translational psychiatry Medium 32839459

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proceedings of the National Academy of Sciences of the United States of America 1097 15210974
2006 SV2 is the protein receptor for botulinum neurotoxin A. Science (New York, N.Y.) 581 16543415
1999 Abnormal neurotransmission in mice lacking synaptic vesicle protein 2A (SV2A). Proceedings of the National Academy of Sciences of the United States of America 340 10611374
1994 Differential expression of synaptic vesicle protein 2 (SV2) isoforms. The Journal of neuroscience : the official journal of the Society for Neuroscience 324 8083732
1992 The synaptic vesicle protein SV2 is a novel type of transmembrane transporter. Cell 246 1355409
1992 SV2, a brain synaptic vesicle protein homologous to bacterial transporters. Science (New York, N.Y.) 225 1519064
2008 Glycosylated SV2A and SV2B mediate the entry of botulinum neurotoxin E into neurons. Molecular biology of the cell 195 18815274
2011 Binding characteristics of brivaracetam, a selective, high affinity SV2A ligand in rat, mouse and human brain: relationship to anti-convulsant properties. European journal of pharmacology 188 21575627
2020 Synaptic density marker SV2A is reduced in schizophrenia patients and unaffected by antipsychotics in rats. Nature communications 185 31937764
2008 Anti-convulsive and anti-epileptic properties of brivaracetam (ucb 34714), a high-affinity ligand for the synaptic vesicle protein, SV2A. British journal of pharmacology 185 18500360
2001 SV2 modulates the size of the readily releasable pool of secretory vesicles. Nature cell biology 174 11483953
2009 SV2 renders primed synaptic vesicles competent for Ca2+ -induced exocytosis. The Journal of neuroscience : the official journal of the Society for Neuroscience 143 19176798
2010 Cotrafficking of SV2 and synaptotagmin at the synapse. The Journal of neuroscience : the official journal of the Society for Neuroscience 133 20410110
2007 SV2A protein is a broad-spectrum anticonvulsant target: functional correlation between protein binding and seizure protection in models of both partial and generalized epilepsy. Neuropharmacology 133 18207204
1996 Isoform-specific, calcium-regulated interaction of the synaptic vesicle proteins SV2 and synaptotagmin. The Journal of biological chemistry 131 8910372
2009 Botulinum neurotoxins C, E and F bind gangliosides via a conserved binding site prior to stimulation-dependent uptake with botulinum neurotoxin F utilising the three isoforms of SV2 as second receptor. Journal of neurochemistry 129 19650874
2015 Brivaracetam, a selective high-affinity synaptic vesicle protein 2A (SV2A) ligand with preclinical evidence of high brain permeability and fast onset of action. Epilepsia 126 26663401
2009 Glycosylated SV2 and gangliosides as dual receptors for botulinum neurotoxin serotype F. Biochemistry 122 19476346
2006 Binding characteristics of levetiracetam to synaptic vesicle protein 2A (SV2A) in human brain and in CHO cells expressing the human recombinant protein. European journal of pharmacology 122 16556440
2016 Brivaracetam: Rationale for discovery and preclinical profile of a selective SV2A ligand for epilepsy treatment. Epilepsia 121 26920914
2010 SV2 regulates neurotransmitter release via multiple mechanisms. American journal of physiology. Cell physiology 118 20702688
2011 Botulinum neurotoxin D uses synaptic vesicle protein SV2 and gangliosides as receptors. PLoS pathogens 112 21483489
2010 SV2 mediates entry of tetanus neurotoxin into central neurons. PLoS pathogens 99 21124874
2010 SV2 acts via presynaptic calcium to regulate neurotransmitter release. Neuron 97 20620874
2007 Pharmacokinetics and metabolism of 14C-brivaracetam, a novel SV2A ligand, in healthy subjects. Drug metabolism and disposition: the biological fate of chemicals 97 17908923
2016 N-linked glycosylation of SV2 is required for binding and uptake of botulinum neurotoxin A. Nature structural & molecular biology 93 27294781
2009 Proepileptic phenotype of SV2A-deficient mice is associated with reduced anticonvulsant efficacy of levetiracetam. Epilepsia 92 19486357
1993 The SV2 protein of synaptic vesicles is a keratan sulfate proteoglycan. Journal of neurochemistry 92 7685814
2018 Quantifying SV2A density and drug occupancy in the human brain using [11C]UCB-J PET imaging and subcortical white matter as reference tissue. European journal of nuclear medicine and molecular imaging 83 30121895
2005 SV2A and SV2C contain a unique synaptotagmin-binding site. Molecular and cellular neurosciences 74 15866046
1993 The synaptic vesicle proteins SV2, synaptotagmin and synaptophysin are sorted to separate cellular compartments in CHO fibroblasts. The Journal of cell biology 71 7901222
1996 Subcellular localization of SV2 and other secretory vesicle components in PC12 cells by an efficient method of preembedding EM immunocytochemistry for cell cultures. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 62 8985140
2022 Imaging the effect of ketamine on synaptic density (SV2A) in the living brain. Molecular psychiatry 61 35165397
1994 Light and electron microscopic analysis of synaptic development in Macaca monkey retina as detected by immunocytochemical labeling for the synaptic vesicle protein, SV2. The Journal of comparative neurology 60 8144745
2014 Expression pattern of synaptic vesicle protein 2 (SV2) isoforms in patients with temporal lobe epilepsy and hippocampal sclerosis. Neuropathology and applied neurobiology 59 23617838
1989 Most synaptic vesicles isolated from rat brain carry three membrane proteins, SV2, synaptophysin, and p65. Journal of neurochemistry 59 2496198
2015 Overlapping functions of stonin 2 and SV2 in sorting of the calcium sensor synaptotagmin 1 to synaptic vesicles. Proceedings of the National Academy of Sciences of the United States of America 57 26015569
2016 Synaptic vesicle glycoprotein 2A (SV2A) regulates kindling epileptogenesis via GABAergic neurotransmission. Scientific reports 56 27265781
2019 Development and In Vivo Preclinical Imaging of Fluorine-18-Labeled Synaptic Vesicle Protein 2A (SV2A) PET Tracers. Molecular imaging and biology 55 30084043
2014 Discovery of heterocyclic nonacetamide synaptic vesicle protein 2A (SV2A) ligands with single-digit nanomolar potency: opening avenues towards the first SV2A positron emission tomography (PET) ligands. ChemMedChem 55 24446373
2011 Levetiracetam reverses synaptic deficits produced by overexpression of SV2A. PloS one 52 22220214
2016 A Mitochondrial Role of SV2a Protein in Aging and Alzheimer's Disease: Studies with Levetiracetam. Journal of Alzheimer's disease : JAD 50 26639968
2013 Expression of SV2 isoforms during rodent brain development. BMC neuroscience 49 23937191
2005 SV2A and SV2C are not vesicular Ca2+ transporters but control glucose-evoked granule recruitment. Journal of cell science 49 16306227
2012 Glycosylation is dispensable for sorting of synaptotagmin 1 but is critical for targeting of SV2 and synaptophysin to recycling synaptic vesicles. The Journal of biological chemistry 47 22908222
2014 The human synaptic vesicle protein, SV2A, functions as a galactose transporter in Saccharomyces cerevisiae. The Journal of biological chemistry 45 25326386
2007 Levetiracetam: the first SV2A ligand for the treatment of epilepsy. Expert opinion on drug discovery 45 23484603
2000 The synaptic vesicle protein SV2 is complexed with an alpha5-containing laminin on the nerve terminal surface. The Journal of biological chemistry 45 10617638
2020 Synaptic dysfunction induced by glycine-alanine dipeptides in C9orf72-ALS/FTD is rescued by SV2 replenishment. EMBO molecular medicine 43 32347002
2019 Synthesis and in vivo evaluation of [18F]UCB-J for PET imaging of synaptic vesicle glycoprotein 2A (SV2A). European journal of nuclear medicine and molecular imaging 43 31175396
2015 Biodistribution and Radiation Dosimetry for the Novel SV2A Radiotracer [(18)F]UCB-H: First-in-Human Study. Molecular imaging and biology 42 25595813
2014 Radiosynthesis of (11)C-Levetiracetam: A Potential Marker for PET Imaging of SV2A Expression. ACS medicinal chemistry letters 40 25313330
2013 Identification of the SV2 protein receptor-binding site of botulinum neurotoxin type E. The Biochemical journal 40 23621114
2009 Preferential increase in the hippocampal synaptic vesicle protein 2A (SV2A) by pentylenetetrazole kindling. Biochemical and biophysical research communications 36 19751703
2020 Distinct synaptic vesicle recycling in inhibitory nerve terminals is coordinated by SV2A. Progress in neurobiology 35 32615146
2012 Altered balance between excitatory and inhibitory inputs onto CA1 pyramidal neurons from SV2A-deficient but not SV2B-deficient mice. Journal of neuroscience research 35 22847229
2010 The SV2 variant of KLF6 is down-regulated in hepatocellular carcinoma and displays anti-proliferative and pro-apoptotic functions. Journal of hepatology 34 20801538
2013 Preclinical radiation dosimetry for the novel SV2A radiotracer [18F]UCB-H. EJNMMI research 33 23647774
1993 Conservation of the amino acid sequence of SV2, a transmembrane transporter in synaptic vesicles and endocrine cells. Gene 33 8299963
2012 Analysis of Synaptotagmin, SV2, and Rab3 Expression in Cortical Glutamatergic and GABAergic Axon Terminals. Frontiers in cellular neuroscience 32 22275882
2019 Increased Inflammation and Unchanged Density of Synaptic Vesicle Glycoprotein 2A (SV2A) in the Postmortem Frontal Cortex of Alzheimer's Disease Patients. Frontiers in cellular neuroscience 31 31866830
2018 SV2: accurate structural variation genotyping and de novo mutation detection from whole genomes. Bioinformatics (Oxford, England) 31 29300834
2013 Amyloid beta a4 precursor protein-binding family B member 1 (FE65) interactomics revealed synaptic vesicle glycoprotein 2A (SV2A) and sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) as new binding proteins in the human brain. Molecular & cellular proteomics : MCP 31 24284412
2011 Epilepsy caused by an abnormal alternative splicing with dosage effect of the SV2A gene in a chicken model. PloS one 31 22046416
2011 Increased levels of SV2A botulinum neurotoxin receptor in clinical sensory disorders and functional effects of botulinum toxins A and E in cultured human sensory neurons. Journal of pain research 31 22090803
2016 Botulinum Neurotoxin Serotype A Recognizes Its Protein Receptor SV2 by a Different Mechanism than Botulinum Neurotoxin B Synaptotagmin. Toxins 30 27196927
2020 In vivo imaging of synaptic SV2A protein density in healthy and striatal-lesioned rats with [11C]UCB-J PET. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 29 32538280
2024 Tracing synaptic loss in Alzheimer's brain with SV2A PET-tracer UCB-J. Alzheimer's & dementia : the journal of the Alzheimer's Association 28 38363009
2023 Presynaptic targeting of botulinum neurotoxin type A requires a tripartite PSG-Syt1-SV2 plasma membrane nanocluster for synaptic vesicle entry. The EMBO journal 28 37226896
1998 Synaptic vesicle protein SV2B, but not SV2A, is predominantly expressed and associated with microvesicles in rat pinealocytes. Journal of neurochemistry 28 9648885
2020 An Epilepsy-Associated SV2A Mutation Disrupts Synaptotagmin-1 Expression and Activity-Dependent Trafficking. The Journal of neuroscience : the official journal of the Society for Neuroscience 27 32341095
2008 No major role of common SV2A variation for predisposition or levetiracetam response in epilepsy. Epilepsy research 27 18977120
2016 A Missense Mutation of the Gene Encoding Synaptic Vesicle Glycoprotein 2A (SV2A) Confers Seizure Susceptibility by Disrupting Amygdalar Synaptic GABA Release. Frontiers in pharmacology 26 27471467
2008 Visualization of SV2A conformations in situ by the use of Protein Tomography. Biochemical and biophysical research communications 26 18692481
2020 Quantification of SV2A Binding in Rodent Brain Using [18F]SynVesT-1 and PET Imaging. Molecular imaging and biology 25 33258040
2011 Insecticidal potency of bacterial species Bacillus thuringiensis SV2 and Serratia nematodiphila SV6 against larvae of mosquito species Aedes aegypti, Anopheles stephensi, and Culex quinquefasciatus. Parasitology research 25 22065062
2017 Therapeutic Role of Synaptic Vesicle Glycoprotein 2A (SV2A) in Modulating Epileptogenesis. CNS & neurological disorders drug targets 24 28393712
2018 Expression of KLF6-SV2 in colorectal cancer and its impact on proliferation and apoptosis. European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation (ECP) 23 29084019
2015 Exploring the interaction of SV2A with racetams using homology modelling, molecular dynamics and site-directed mutagenesis. PloS one 23 25692762
2013 Modulation of the conformational state of the SV2A protein by an allosteric mechanism as evidenced by ligand binding assays. British journal of pharmacology 23 23530581
2012 Kindling-associated SV2A expression in hilar GABAergic interneurons of the mouse dentate gyrus. Neuroscience letters 23 22266237
2002 Expression of synaptic vesicle protein 2 (SV2) in neuroendocrine tumours of the gastrointestinal tract and pancreas. The Journal of pathology 23 11748641
1996 Mapping the innervation of the bronchial tree in fetal and postnatal pig lung using antibodies to PGP 9.5 and SV2. American journal of respiratory cell and molecular biology 23 8969263
2019 Differential expression of SV2A in hippocampal glutamatergic and GABAergic terminals during postnatal development. Brain research 22 30905653
2002 Neoplastic transformation of human lung fibroblast MRC-5 SV2 cells induced by benzo[a]pyrene and confluence culture. Cancer research 22 12183415
2023 Development of SV2A Ligands for Epilepsy Treatment: A Review of Levetiracetam, Brivaracetam, and Padsevonil. Neuroscience bulletin 21 37897555
2020 Exploring with [18F]UCB-H the in vivo Variations in SV2A Expression through the Kainic Acid Rat Model of Temporal Lobe Epilepsy. Molecular imaging and biology 21 32206990
2024 SV2A PET imaging in human neurodegenerative diseases. Frontiers in aging neuroscience 19 38699560
2024 Presynaptic density determined by SV2A PET is closely associated with postsynaptic metabotropic glutamate receptor 5 availability and independent of amyloid pathology in early cognitive impairment. Alzheimer's & dementia : the journal of the Alzheimer's Association 18 38634334
2014 Hippocampal low-frequency stimulation increased SV2A expression and inhibited the seizure degree in pharmacoresistant amygdala-kindling epileptic rats. Epilepsy research 18 25205164
2019 Mode of seizure inhibition by sodium channel blockers, an SV2A ligand, and an AMPA receptor antagonist in a rat amygdala kindling model. Epilepsy research 16 31035244
2023 Longitudinal Imaging of Regional Brain Volumes, SV2A, and Glucose Metabolism In Huntington's Disease. Movement disorders : official journal of the Movement Disorder Society 15 37382295
2024 Structural basis for antiepileptic drugs and botulinum neurotoxin recognition of SV2A. Nature communications 14 38637505
2024 Comprehensive mapping of synaptic vesicle protein 2A (SV2A) in health and neurodegenerative diseases: a comparative analysis with synaptophysin and ground truth for PET-imaging interpretation. Acta neuropathologica 14 39476256
2021 Validation of SV2A-Targeted PET Imaging for Noninvasive Assessment of Neuroendocrine Differentiation in Prostate Cancer. International journal of molecular sciences 14 34884893
2020 Integration of postmortem amygdala expression profiling, GWAS, and functional cell culture assays: neuroticism-associated synaptic vesicle glycoprotein 2A (SV2A) gene is regulated by miR-133a and miR-218. Translational psychiatry 14 32839459
2019 Levetiracetam-induced a new seizure type in a girl with a novel SV2A gene mutation. Clinical neurology and neurosurgery 14 31005049
2016 Development and Validation of a New Mouse Model to Investigate the Role of SV2A in Epilepsy. PloS one 14 27861538
2021 Effects of chronic exposure to haloperidol, olanzapine or lithium on SV2A and NLGN synaptic puncta in the rat frontal cortex. Behavioural brain research 13 33636238
2009 SV2 frustrating exocytosis at the semi-diffusor synapse. Synapse (New York, N.Y.) 13 19140166

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