Disease relevance of SYT1

• The cytoplasmic domains of human and Drosophila synaptotagmins produced as recombinant proteins in Escherichia coli specifically bound phosphatidylserine similar to rat synaptotagmin [1].
• Botulinum neurotoxin A activity is dependent upon the presence of specific gangliosides in neuroblastoma cells expressing synaptotagmin I [2].
• Synaptotagmin I expression in mast cells of normal human tissues, systemic mast cell disease, and a human mast cell leukemia cell line [3].
• Cell surface antigens (p61 and p65) encoded by HTLV-I are frequently recognized, at low titers, by antibodies in the serum of patients with acquired immunodeficiency syndrome (AIDS) or with signs or symptoms that precede AIDS (pre-AIDS) [4].
• Using a double-stranded RNA interference approach, we demonstrated that preventing the hypoxia inducible HSP70 enhanced down-regulation of syntaxin and synaptotagmin, and aggravated motor and sensory suppression [5].

Psychiatry related information on SYT1

• Synaptosomal proteins, beta-soluble N-ethylmaleimide-sensitive factor attachment protein (beta-SNAP), gamma-SNAP and synaptotagmin I in brain of patients with Down syndrome and Alzheimer's disease [6].
• Role of nigral NFkappaB p50 and p65 subunit expression in haloperidol-induced neurotoxicity and stereotyped behavior in rats [7].
• Acute alcohol consumption inhibited LPS-induced DNA binding of the p65/p50 NF-kappaB in monocytes that regulates the expression of both the TNF-alpha and the IL-1beta genes [8].
• No significant differences occurred in corticosterone and ACTH levels following air-puff startle or in pain thresholds at P65 between N4 and T4 groups [9].
• Pain thresholds were measured on P16, P22, and P65 (hot-plate test), and testing for defensive withdrawal, alcohol preference, air-puff startle, and social discrimination tests occurred during adulthood [9].

High impact information on SYT1

• Ca(2+) binding to synaptotagmin 1 triggers fast exocytosis of synaptic vesicles that have been primed for release by SNARE-complex assembly [10].
• Besides synaptotagmin 1, fast Ca(2+)-triggered exocytosis requires complexins [10].
• Here we propose that complexin binding activates SNARE complexes into a metastable state and that Ca(2+) binding to synaptotagmin 1 triggers fast exocytosis by displacing complexin from metastable SNARE complexes [10].
• METHODS: We analyzed SYT-SSX fusion transcripts in 45 synovial sarcomas (33 monophasic and 12 biphasic) by the reverse-transcriptase polymerase chain reaction and compared the results with relevant clinical and pathological data [11].
• SYT-SSX gene fusion as a determinant of morphology and prognosis in synovial sarcoma [11].

Chemical compound and disease context of SYT1

• Local administration of p65 antisense phosphorothioate oligonucleotides abrogated clinical and histological signs of colitis and was more effective in treating TNBS-induced colitis than single or daily administration of glucocorticoids [12].
• A family of serine proteases expressed exclusively in myelo-monocytic cells specifically processes the nuclear factor-kappa B subunit p65 in vitro and may impair human immunodeficiency virus replication in these cells [13].
• Initially, we noted that the overexpression of MDM2 protein in leukemic bone marrow cells of patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL), and an ALL cell line (EU-4) transfected with the MDM2 gene was associated with elevated expression of p65 and in vitro resistance to doxorubicin (Adriamycin) [14].
• We have previously shown that cox-2 is transcriptionally regulated by hypoxia in human umbilical vein endothelial cells (HUVEC) in culture via the transactivation factor NF-kappaB p65, leading to increased production of prostaglandin E(2), an inhibitor of vascular smooth muscle cell proliferation [15].
• Overexpression of p65/RelA potentiates curcumin-induced apoptosis in HCT116 human colon cancer cells [16].

Biological context of SYT1

• The comparative mapping data confirm the relative inversion of gene order of SYT1 compared with humans and mice [17].
• BP1 was found to be closer to the centromere than either BM6026 or SYT1 with two standard computer software packages for analyzing radiation hybrid panel data [17].
• Previous studies found that SV2A, but not SV2B, can interact with the cytoplasmic domain of synaptotagmin 1, a Ca2+ sensor for synaptic vesicle exocytosis [18].
• The human gene for synaptotagmin was mapped by Southern blot analysis of DNA from somatic cell hybrids to chromosome 12 region cen-q21, and the Drosophila gene by in situ hybridization to 23B [1].
• Hemagglutination was inhibited both by negatively charged phospholipids and by a recombinant fragment from rat synaptotagmin that contained only a single copy of the two internal repeats [1].

Anatomical context of SYT1

• In vivo confocal imaging of oocytes revealed GFP-synaptotagmin at the plasma membrane when the channel was present, as opposed to random distribution in its absence, consistent with Ca(2+)-independent molecular link of synaptotagmin and the channel [19].
• Both imaging studies and protein-protein interactions in Xenopus oocytes show that channel linkage to synaptotagmin precedes Ca(2+) influx [19].
• Whereas both cell lines expressed synaptotagmin I, SNAP-25 cleavage was not observed in the absence of complex gangliosides [2].
• Fatty acylation of synaptotagmin in PC12 cells and synaptosomes [20].
• Here we demonstrate that synaptotagmin I covalently incorporated [3H]palmitate after metabolic labelling of PC-12 cells and rat brain synaptosomes [20].

Associations of SYT1 with chemical compounds

• Synaptotagmin I (STG I) is a Ca(2+) sensor and one of the synaptic vesicle proteins that mediate exocytosis [3].
• Using a combination of competition and direct binding assays, we demonstrate that synaptotagmin I, an intrinsic membrane protein of synaptic vesicles, has all of the properties of the AP-2 receptor and that AP-2 binds to the second C2 domain in the molecule [21].
• To test the effect of synaptotagmin I on membrane fusion, we incorporated it into a SNARE-mediated liposome fusion assay [22].
• Utilization of antisense technology showed that p65 but not p50 or c-Rel mediated IL-1beta-stimulated PGE2 formation [23].
• Notably, the binding activity to phosphatidylserine is inhibited by a physiological range of the Ca(2+) concentration attained after secretagogue stimulation, which presents a striking contrast to the Ca(2+)-stimulatory activity of the C2A domain of synaptotagmin I [24].

Physical interactions of SYT1

• In synaptic vesicles, synaptotagmin-12 forms a complex with synaptotagmin-1 that prevents synaptotagmin-1 from interacting with SNARE complexes [25].
• Interestingly, stimulated IL-8 production was not inhibited by the classical NFkappaB decoy but was reduced by treatment with antisense to both p65 and c-Rel supporting preferential binding of c-Rel-p65 to the "alternative" IL-8 kappaB motif [23].
• Dvl inhibited the binding of Syt I to the complex consisting of syntaxin-1A and SNAP-25 [26].
• We also demonstrate that it does not participate directly in Cav2.1 Ca2+ channel gating but serves as a binding site in protein-protein interactions with synaptotagmin I and the LC2 domain of microtubule-associated protein 1A [27].
• Models of the two zinc-binding modules of PKC alpha are based on nuclear magnetic resonance and crystal structures of such modules in other PKC isoforms while the calcium phospholipid binding module (C2) is based on the crystal structure of a repeating unit in synaptotagmin I [28].

Regulatory relationships of SYT1

• Synaptotagmin was detected at the membrane also in oocytes co-expressing the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) [19].
• This impairment, however, is less severe than that produced in forebrain neurons by deletion of synaptotagmin-1, presumably because at least in NMJs, synaptotagmin-1 is coexpressed with synaptotagmin-2, and both together mediate fast Ca2+-triggered release [29].
• The WNK kinases may be able to influence ion homeostasis through its effects on synaptotagmin function [30].
• However, a mutant form of the receptor lacking a potential AP-2 recruitment motif, while being internalized normally in response to agonist stimulation, was not rescued by synaptotagmin in cells expressing dominant-negative dynamin or arrestin [31].

Other interactions of SYT1

• It is well established that syntaxin 1A, synaptosomal-associated protein of 25 kDa (SNAP-25) and synaptotagmin either alone or in combination, modulate the kinetic properties of voltage-gated Ca(2+) channels Ca(v)1.2 (Lc-channel) Ca(v)2.2 (N-type) and Ca(v)2.1 (P/Q-type) [19].
• Co-expression of Ca(v)2.3 with syntaxin 1A, SNAP-25 and synaptotagmin together, produced a channel with distinctive kinetic properties analogous to excitosome multiprotein complex generated by Ca(v)1.2 and Ca(v)2 [19].
• Thus, synaptotagmin-2 is an essential synaptotagmin isoform that functions in concert with other synaptotagmins in the Ca2+ triggering of neurotransmitter release [29].
• S100A13 is involved in the regulation of fibroblast growth factor-1 and p40 synaptotagmin-1 release in vitro [32].
• The p52/p65 heterodimer formed in the nucleus, bound specifically to the promoter of the tumor suppressor protein p53, effecting a 25 to 30-fold increase in the level of this protein [33].

Analytical, diagnostic and therapeutic context of SYT1

• The well-characterized synaptotagmin isoforms I and II are present in pancreatic beta-cell lines RINm5F, INS-1 and HIT-T15 as shown by Northern and Western blots [34].
• 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 [5].
• In an earlier study performed by us, one synaptic vesicle specific protein, synaptotagmin, was detected in CSF for the first time using a procedure based on affinity chromatography, reversed-phase chromatography, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and chemiluminescence immunoblotting [35].
• Co-immunoprecipitation experiments indicated that syntaxin can form a complex with synaptotagmin and calcium channels [36].
• To investigate the molecular mechanisms involved in synaptic remodeling during the estrous cycle, we analyzed the expression of three presynaptic markers, synaptotagmin I, synaptotagmin IV, and synaptophysin, in the female adult rat brain by in situ hybridization [37].

References