Disease relevance of Syt1

• The data provide direct evidence for the central importance of p65 in chronic intestinal inflammation and suggest a potential therapeutic utility of p65 antisense oligonucleotides as a novel molecular approach for the treatment of patients with Crohn's disease [1].
• An infrequent (2-3%) B lymphocyte subpopulation was found in the normal human tonsil and lymph nodes that shows the phenotypic characteristics of B-chronic lymphocytic leukemia (B-CLL) (rosette formation with mouse erythrocytes, weak expression of membrane Ig, staining for HLA-DR, and OKT1 or Leu-1 detecting a T cell-associated p65 antigen) [2].
• In 2 variations of the model an antisense oligonucleotide for nuclear factor kappa B (NF-kappa B) p65 was given prophylactically or therapeutically to block chronic inflammation-associated fibrosis [3].
• The synaptic vesicle protein synaptotagmin associates with calcium channels and is a putative Lambert-Eaton myasthenic syndrome antigen [4].
• Conversely, activation of the mouse mammary tumor virus promoter by a combination of dexamethasone and glucocorticoid receptor is inhibited by overexpression of p65 [5].

Psychiatry related information on Syt1

• Consistent with the idea that the Syt IV mutation preferentially affects hippocampal function, Syt IV mutant mice also display impaired social transmission of food preference [6].

High impact information on Syt1

• KIF1A was associated with organelles that contained synaptic vesicle proteins such as synaptotagmin, synaptophysin, and Rab3A [7].
• When introduced by homologous recombination into the endogenous synaptotagmin I gene in mice, this point mutation decreases the Ca2+ sensitivity of neurotransmitter release twofold, but does not alter spontaneous release or the size of the readily releasable pool of neurotransmitters [8].
• Here we report the crystal structure at 2.9 A resolution of the p50/p65 heterodimer bound to the kappaB DNA of the intronic enhancer of the immunoglobulin light-chain gene [9].
• The NF-kappaB family members p65 (RelA) and c-Rel recognize similar DNA sequences, yet the phenotypes of mutant mice suggest that these proteins regulate distinct sets of genes [10].
• Overexpression of p65 increases endogenous I kappa B protein in both carcinoma and lymphoid cells by two mechanisms: protein stabilization and increased transcription of I kappa B mRNA [11].

Chemical compound and disease context of Syt1

• Molecular basis of complement resistance of human melanoma cells expressing the C3-cleaving membrane protease p65 [12].
• We examined the effect of antisense oligonucleotides to the p65 subunit of NF-kappaB on the survival of bleomycin (BLM)-induced pneumonitis in C57BL/6 mice (female, 8 wk of age, 17 to 20 g body weight) [13].
• The effect of intracolonically administered NF-kappaB (p65) antisense phosphorothioate oligonucleotide was examined in mouse DSS-induced colitis using drinking water containing 5% DSS [14].
• These findings suggest that the suppression of cytokines and mediators in monocytes and alveolar macrophages by the antisense oligonucleotide to the p65 subunit of NF-kappaB worsens the survival of LPS-induced ARDS in mice with the progress of hemorrhagic lung edema [15].
• To investigate which viral proteinase may be responsible for generating p72 and p65, we expressed the 5'-region of the MHV-JHM RNA polymerase gene including the two papain-like cysteine proteinase domains in an in vitro transcription/translation system and analyzed the translation products for proteolytic processing [16].

Biological context of Syt1

• By overexpression of Syt1 mutated in the shared PKC/calcium/calmodulin-dependent kinase phosphorylation site, we show that phorbol esters act independently and upstream of Syt1 to regulate the size of the releasable pools [17].
• We conclude that exocytosis from mouse chromaffin cells can be modified by the differential expression of Syt isoforms and by Syt abundance but not by phosphorylation of Syt1 [17].
• The RRP was also rescued by Syt2 overexpression, but the kinetics of fusion was slightly slower than in cells expressing Syt1 [17].
• Syt II protein coding regions consist of 8 exons with a total size of about 7 kbp [18].
• Taken together, our data suggest a critical role for Syt VIII and Stx2 in membrane fusion and acrosome reaction in the sperm [19].

Anatomical context of Syt1

• Chromaffin cells express Syt1 but not Syt2 [17].
• High time-resolution capacitance measurement showed that Syt1 null cells lack the exocytotic phase corresponding to the readily-releasable pool (RRP) of vesicles [17].
• Our data suggest that synaptotagmin 1 and 2 perform equivalent functions in the Ca2+ triggering of action potential-induced release and in the restriction of spontaneous release, consistent with a general role of synaptotagmins in controlling 'release slots' for synaptic vesicles at the active zone [20].
• Synaptotagmin 2 resembles synaptotagmin 1, the Ca2+ sensor for fast neurotransmitter release in forebrain synapses, but little is known about synaptotagmin 2 function [20].
• Polypeptide sequence analysis revealed that this heparin-binding protein corresponded to the extravesicular domain of bovine synaptotagmin (Syn)-1, a transmembrane component of synaptic vesicles involved in the regulation of organelle traffic [21].

Associations of Syt1 with chemical compounds

• Synaptotagmin (Syt) I (or II) is thought to be a Ca(2+) sensor for neurotransmitter release in the rostral (or caudal) region of the mammalian brain [18].
• The developmental expression of synaptotagmin 1, a well characterized glycoprotein of synaptic vesicle, was determined by immunoblots analysis [22].
• Rabphilin 3A, another neuronal protein containing C2 domains, cannot bind IP4, indicating that the IP4 binding property is specific to the C2B domain of synaptotagmin [23].
• We now show that in cultured cortical neurons stimulated at low frequency (<or.1 Hz), deletion of synaptotagmin 1 blocks synchronous GABA and glutamate release without significantly increasing asynchronous release [24].
• Ca(2+) induces binding of the synaptotagmin C(2) domains to SNARE proteins, whereas Sr(2+) even at high concentrations does not [25].

Physical interactions of Syt1

• Biochemical experiments showed that Syt2 has a slightly lower Ca2+ affinity for phospholipid binding than Syt1 because of a difference in the C2A domain [17].
• We found that Stx2 binds to Syt I, VI, and VIII in a calcium-dependent manner with EC(50) values of 175, 233, and 96 mum calcium, respectively [19].

Other interactions of Syt1

• Distribution of the presynaptic calcium sensors, synaptotagmin I/II and synaptotagmin III, in the goldfish and rodent retinas [26].
• The extravesicular domain of synaptotagmin-1 is released with the latent fibroblast growth factor-1 homodimer in response to heat shock [21].
• In the docking assay, addition of Ca2+ induces the formation of a SNAP-25-Synaptotagmin 1 complex [27].
• Furthermore, Snapin is relatively enriched in the purified large dense-core vesicles of chromaffin cells and associated with synaptotagmin-1 [28].
• Mass spectrometry of crosslinked synaptotagmin . p97/VCP revealed interactions near Trp551 and Phe552 [29].

Analytical, diagnostic and therapeutic context of Syt1

• Here, using synapto-pHluorin in an approach that allows the dissection of endocytosis and exocytosis into separate components during periods of stimulation, we examined exocytic-endocytic coupling in synapses from SytI knockout mice and their WT littermates [30].
• The distributions of the two synaptic vesicle proteins p65 [Matthew et al. (1981) J. Cell Biol., 91:257-269] and synapsin I [De Camilli et al. (1983) J. Cell Biol., 96:1337-1354] were compared in macaque monkey retina using pre-embedding immunocytochemistry for both light and electron microscopy [31].
• Surprisingly, simultaneous transplantation of wild-type bone marrow cells rescued the production of p50/p65-deficient lymphocytes [32].
• Similarly, in co-cultures of Schwann cells and sensory neurons, NF-kappaB activation paralleled myelination, and blocking its activity or using cells from mice lacking the NF-kappaB subunit p65 markedly attenuated myelination [33].
• In cell culture models, apoptosis is contingent upon a mechanism involving reovirus-induced activation of transcription factor NF-kappaB complexes containing p50 and p65/RelA subunits [34].

References