Disease relevance of SV2A

• Semiquantitative immunoblotting analyses showed that hypoxia exposure induced increased expression of heat-shock protein (HSP)70 in ganglion preparations, and suppressed expression of the presynaptic proteins syntaxin I, synaptic vesicle protein 2 (SV2) and synaptotagmin I [1].
• The staining patterns with the three markers agreed well, except in hindgut carcinoids, which showed strong SV2 immunoreactivity, weak synaptophysin but no chromogranin A immunostaining [2].
• In pituitary adenomas more cells were immunoreactive to SV2 than to the other two antibodies [2] .
• SV2 labelling was also demonstrated in gastrointestinal pacemaker cell tumours (8/8), while adenocarcinomas of the gastrointestinal tract and pancreas were negative, with the exception of occasional adenocarcinomas demonstrating weak SV2 labelling (stomach 1/22, rectum 1/29, and pancreas 0/21) [3].

High impact information on SV2A

• Here, we show that the synaptic vesicle protein SV2A is the brain binding site of levetiracetam (LEV), a new antiepileptic drug with a unique activity profile in animal models of seizure and epilepsy [4].
• The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam [4].
• Brain membranes and purified synaptic vesicles from mice lacking SV2A do not bind a tritiated LEV derivative, indicating that SV2A is necessary for LEV binding [4].
• Furthermore, there is a high degree of correlation between binding affinities of a series of LEV derivatives to SV2A in fibroblasts and to the LEV-binding site in brain [4].
• Further, these results indicate that proteins involved in vesicle exocytosis, and SV2 in particular, are promising targets for the development of new CNS drug therapies [4].

Chemical compound and disease context of SV2A [5].

Biological context of SV2A

• SV2A and SV2B have been shown to be involved in the regulation of synaptic vesicle exocytosis [6].
• It cannot be explained by putative binding of [3H]ucb 30889 to SV2B or C isoforms but may reflect different patterns of SV2A glycosylation or the formation of SV2A oligomers [7].
• Detailed time course analyses showed that an early moderate increase developed within 6 h, preceding a substantial up-regulation of HSP70 after 4 days; an early reduction of syntaxin I in the first 24 h; a delayed reduction of synaptotagmin I after 4 days; and a biphasic change in SV2 [1].
• Two distinct cDNAs that appear to encode proteins in the synaptic vesicle-2 (SV2) family were identified as expressed sequence tags from a Ctenocephalides felis hindgut and Malpighian tubule (HMT) cDNA library [8]. [9].

Anatomical context of SV2A

• We found an excellent correlation between the affinities of these compounds measured in human brain, rat brain and CHO cells expressing human SV2A [7].
• Saturation binding curves led to Kd values for [3H]ucb 30889 of 53+/-7, 55+/-9, 70+/-11 and 75+/-33 nM in human cerebral cortex, hippocampus, cerebellum and CHO cells expressing SV2A respectively [7].
• By using a monoclonal antibody to SV2, immunoreactivities were demonstrated in NE cell types in human gastrointestinal tract, pancreas, anterior pituitary gland, thyroid, parathyroid, and adrenal medulla, and also in chief cells of gastric oxyntic mucosa [2] .
• Immunoelectron microscopy of pancreatic islets revealed SV2 immunoreactivity in secretory granules [2].

Associations of SV2A with chemical compounds

• Competition experiments were performed to determine the affinities for SV2A of a variety of compounds including levetiracetam, some of its analogues and other molecules known to interact with levetiracetam binding sites in rat brain such as bemegride, pentylenetetrazol and chlordiazepoxide [7].
• Electrophysiological studies of spontaneous inhibitory neurotransmission in the CA3 region of the hippocampus revealed that loss of SV2A leads to a reduction in action potential-dependent gamma-aminobutyric acid (GABA)ergic neurotransmission [10].
• N-dodecyl-beta-D-maltoside (DDM) was the best detergent at achieving a high percentage of SV2A solubilization and at maintaining the binding characteristics of a tritiated form of a more potent analogue of LEV, [3H]ucb 30889 ((2S)-2-[4-(3-azidophenyl)-2-oxopyrrolidin-1-yl]butanamide) [11].
• Synaptic vesicle protein 2 (SV2) is a membrane glycoprotein common to all synaptic and endocrine vesicles [10].
• Molecular cloning of a cDNA encoding synaptic vesicle protein 2 (SV2) revealed that it is homologous to a family of proton cotransporters from bacteria and fungi and to a related family of glucose transporters found in mammals [12].

Other interactions of SV2A

• Our data suggest that closely related members of a synaptic vesicle protein family can either have very general (SV2A) or restricted distributions (SV2C), possibly in order to allow specialization in the regulation of the expression or of the function of these abundant synaptic vesicle proteins [13].
• The distributions of SV2 and synaptophysin, two synaptic vesicle integral membrane proteins, generally followed the distribution of synaptic vesicles, which were typically evenly distributed under control conditions and had a notable depletion in zone III after stimulation [14].

Analytical, diagnostic and therapeutic context of SV2A

• Finally, there is a strong correlation between the affinity of a compound for SV2A and its ability to protect against seizures in an audiogenic mouse animal model of epilepsy [4].
• After immunoprecipitation of SV2A from solubilized rat brain membranes, binding properties of [3H]ucb 30889 to SV2A and association with synaptotagmin I were maintained [11].
• Immunodetection analysis revealed that the synaptic vesicle proteoglycan SV2 is the core of the intravesicular matrix and is responsible for immobilization and release of ACh and ATP [15].
• Paraffin blocks from 211 gastrointestinal tumours were examined by immunocytochemistry, using a monoclonal antibody against SV2 [3].
• Western blotting of tumour biopsies confirmed expression of SV2 in endocrine tumours of the gastrointestinal tract and pancreas [3].

References