The Human Synaptic Vesicle Protein, SV2A, Functions as a Galactose Transporter in Saccharomyces cerevisiae

Madeo, Marianna; Kovács, Attila; Pearce, David A.

doi:10.1074/jbc.c114.584516

Cited by 43 publications

(34 citation statements)

References 28 publications

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“…15 However, it has recently been shown that, in hexosetransport deficient yeast, the human SV2A protein acts as a galactose transporter. 16 This finding could have important implications if extended to mammalian cells. If the SV2A protein is a member of the MFS family, then it should act as a transporter via the alternating access mechanism.…”

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confidence: 88%

“…Therefore, SV2A may function as a transporter, although little evidence supports this, apart from the finding that the SV2A protein acts as the point of entry of botulinum neurotoxin E into neurons . However, it has recently been shown that, in hexose‐transport deficient yeast, the human SV2A protein acts as a galactose transporter . This finding could have important implications if extended to mammalian cells.…”

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confidence: 99%

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Evidence for a differential interaction of brivaracetam and levetiracetam with the synaptic vesicle 2A protein

Wood

Gillard

2016

Epilepsia

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SUMMARYObjective: Brivaracetam (BRV) and levetiracetam (LEV) are effective antiepileptic drugs that bind selectively to the synaptic vesicle 2A (SV2A) protein. However, BRV differs from LEV in that it exhibits more potent and complete seizure suppression in animal models including in amygdala-kindled mice, where BRV afforded nearly complete seizure suppression. This raises the possibility that aside from potency differences, BRV and LEV may interact differently with the SV2A protein, which is not apparent in radioligand-binding competition studies. In this study, we used a recently identified SV2A allosteric modulator, UCB1244283, that appears to induce conformational changes in SV2A, to probe the binding properties of labeled BRV and LEV. The synaptic vesicle 2A (SV2A) protein is an integral transmembrane glycoprotein expressed in neurons and endocrine cells, where it specifically localizes to secretory vesicles.1,2 It is notable that the SV2A protein was shown to bind the antiepileptic drugs (AEDs) levetiracetam 3 (LEV) and brivaracetam 4 (BRV), and was also shown to be the molecular target of their anticonvulsant activity.5 A strong positive correlation has been demonstrated between anticonvulsant potency in animal models and SV2A binding affinity, [4][5][6] and seizure protection correlates with SV2A occupancy. 4 In addition, the anticonvulsant activity of LEV is reduced in SV2A-deficient animals. 6 It has also been shown that LEV reverses the synaptic deficits produced by overexpression of the SV2A protein.7 These data suggest that the incidence of seizures are affected by both increased and decreased expression of SV2A and are reduced by treatment with LEV. Although there is good evidence suggesting that the SV2A protein is the molecular target of action for the antiepileptic drugs BRV and LEV, little is known about the precise function of the SV2A protein or how these drugs may affect SV2A function.A recent review concluded that, although the SV2A protein is involved in normal synaptic vesicle function, its precise role remains unclear. 8 Experimental evidence suggests that the SV2A protein has a role in either regulating synaptic exocytosis or as a vesicular transporter. Different studies have shown that SV2A regulates neurotransmitter release,

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confidence: 88%

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confidence: 99%

Evidence for a differential interaction of brivaracetam and levetiracetam with the synaptic vesicle 2A protein

Wood

Gillard

2016

Epilepsia

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“…Among the various functions proposed are roles in calcium-dependent exocytosis, neurotransmitter loading/retention in synaptic vesicles, and synaptic vesicle priming, as well as transport of vesicle constituents [5]. The latter is supported by homology with the major facilitator superfamily (MFS) of membrane transport proteins [32] and by the suggestion that SV2A is a galactose transporter [33]. Mice lacking SV2A generated by targeted gene disruption [34] appear normal at birth, but do not grow normally; they express seizures and die within 3 weeks, suggesting multiple neural alterations.…”

Section: The Role Of Sv2a In Modulating Neuronal Excitability In the mentioning

confidence: 99%

Synaptic Vesicle Glycoprotein 2A Ligands in the Treatment of Epilepsy and Beyond

Löscher¹,

et al. 2016

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The synaptic vesicle glycoprotein SV2A belongs to the major facilitator superfamily (MFS) of transporters and is an integral constituent of synaptic vesicle membranes. SV2A has been demonstrated to be involved in vesicle trafficking and exocytosis, processes crucial for neurotransmission. The anti-seizure drug levetiracetam was the first ligand to target SV2A and displays a broad spectrum of anti-seizure activity in various preclinical models. Several lines of preclinical and clinical evidence, including genetics and protein expression changes, support an important role of SV2A in epilepsy pathophysiology. While the functional consequences of SV2A ligand binding are not fully elucidated, studies suggest that subsequent SV2A conformational changes may contribute to seizure protection. Conversely, the recently discovered negative SV2A modulators, such as UCB0255, counteract the anti-seizure effect of levetiracetam and display procognitive properties in preclinical models. More broadly, dysfunction of SV2A may also be involved in Alzheimer’s disease and other types of cognitive impairment, suggesting potential novel therapies for levetiracetam and its congeners. Furthermore, emerging data indicate that there may be important roles for two other SV2 isoforms (SV2B and SV2C) in the pathogenesis of epilepsy, as well as other neurodegenerative diseases. Utilization of recently developed SV2A positron emission tomography ligands will strengthen and reinforce the pharmacological evidence that SV2A is a druggable target, and will provide a better understanding of its role in epilepsy and other neurological diseases, aiding in further defining the full therapeutic potential of SV2A modulation.

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“…38 SV2A has been shown to act as a LEV-sensitive galactose-proton cotransporter when expressed in yeast. 17 This raises the possibility that loss of galactose influx through LEV-SV2A binding might mediate a synapsin glycosylation event regulating vesicle mobilization. Indeed, a LEV-induced retardation of vesicle recruitment from the reserve pool was occluded in synapsin I knockout mice.…”

Section: Fm1-43 Destainingmentioning

confidence: 99%

Brivaracetam augments short‐term depression and slows vesicle recycling

Yang

Bognar

et al. 2015

Epilepsia

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SUMMARYObjective: Brivaracetam (BRV) decreases seizure activity in a number of epilepsy models and binds to the synaptic vesicle glycoprotein 2A (SV2A) with a higher affinity than the antiepileptic drug levetiracetam (LEV). Experiments were performed to determine if BRV acted similarly to LEV to induce or augment short-term depression (STD) under high-frequency neuronal stimulation and slow synaptic vesicle recycling. Methods: Electrophysiologic field excitatory postsynaptic potential (fEPSP) recordings were made from CA1 synapses in rat hippocampal slices loaded with BRV or LEV during intrinsic activity or with BRV actively loaded during hypertonic stimulation. STD was examined in response to 5 or 40 Hz stimulus trains. Presynaptic release of FM1-43 was visualized using two-photon microscopy to assess drug effects upon synaptic vesicle mobilization. Results: When hippocampal slices were incubated in 0.1-30 lM BRV or 30 lM-1 mM LEV for 3 h, the relative CA1 field EPSPs decreased over the course of a high-frequency train of stimuli more than for control slices. This STD was frequency-and concentrationdependent, with BRV being 100-fold more potent than LEV. The extent of STD depended on the length of the incubation time for both drugs. Pretreatment with LEV occluded the effects of BRV. Repeated hypertonic sucrose treatments and train stimulation successfully unloaded BRV from recycling vesicles and reversed BRVs effects on STD, as previously reported for LEV. At their maximal concentrations, BRV slowed FM1-43 release to a greater extent than in slices loaded with LEV during prolonged stimulation. Significance: BRV, similar to LEV, entered into recycling synaptic vesicles and produced a frequency-dependent decrement of synaptic transmission at 100-fold lower concentrations than LEV. In addition, BRV slowed synaptic vesicle mobilization more effectively than LEV, suggesting that these drugs may modify multiple functions of the synaptic vesicle protein SV2A to curb synaptic transmission and limit epileptic activity. KEY WORDS: Antiepileptic drugs, Anticonvulsants, Epilepsy, Brivaracetam, Levetiracetam, SV2A, Synaptic vesicle recycling, Short-term depression.Brivaracetam (BRV) is an antiepileptic drug that recently showed positive outcome in phase III clinical trials for treatment of partial-onset seizures.1 BRV and the closely related compounds levetiracetam (LEV) and seletracetam (SEL) bind to synaptic vesicle glycoprotein 2A (SV2A), with BRV affinity about 20-fold greater than LEV.2,3 Several mechanisms have been proposed for the antiepileptic action of LEV, including interference with SV2A or blocking of calcium currents. 4 In contrast, BRV does not bind to calcium channels and its effect on sodium channels does not alter sustained activity.3,5

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The Human Synaptic Vesicle Protein, SV2A, Functions as a Galactose Transporter in Saccharomyces cerevisiae

Cited by 43 publications

References 28 publications

Evidence for a differential interaction of brivaracetam and levetiracetam with the synaptic vesicle 2A protein

Evidence for a differential interaction of brivaracetam and levetiracetam with the synaptic vesicle 2A protein

Synaptic Vesicle Glycoprotein 2A Ligands in the Treatment of Epilepsy and Beyond

Brivaracetam augments short‐term depression and slows vesicle recycling

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