Alternative titles; symbols
HGNC Approved Gene Symbol: SYT7
Cytogenetic location: 11q12.2 Genomic coordinates (GRCh38): 11:61,513,714-61,588,387 (from NCBI)
Synaptotagmins, such as SYT7, are brain-specific calcium-dependent phospholipid-binding proteins that play a role in synaptic exocytosis and neurotransmitter release. See 600782.
While constructing a transcript map of the human chromosomal 11q13 interval associated with Best vitelliform macular dystrophy (153700), By RT-PCR, Li et al. (1995) determined that rat Syt7 is expressed at high levels in brain and is widely distributed in non-neural tissues, particularly heart and lung. Cooper et al. (1998) isolated cDNAs encoding the human homolog of rat synaptotagmin 7. The predicted 403-amino acid human and rat proteins are 98% identical. Northern blot analysis revealed that synaptotagmin 7 is expressed as 4.4- and 7.5-kb mRNAs in a variety of human adult and fetal tissues, including those from different regions of the brain.
Fukuda et al. (2002) identified 1 major and 2 minor isoforms of mouse Syt7. The 2 minor isoforms contain unique insertions in the spacer domain between the transmembrane and C2 domains. Similar results were obtained with respect to human SYT7. Expression of fluorescence-tagged Syt7 in rat pheochromocytoma cells revealed localization in the perinuclear region, where it colocalized with a Golgi marker protein, and localization in the tips of neurites.
By Western blot analysis and immunofluorescence microscopy, Caler et al. (2001) demonstrated expression of a 65-kD SYT7 antigen on membrane lysosomes, and SYT7 colocalized with LAMP1 (153330) on a number of cell types.
Using a method called 'Guilt by Association' (GBA), which searches for novel genes whose expression patterns mimic those of known disease-associated genes, Walker et al. (1999) examined the pairwise coexpression patterns of 40,000 human genes in 522 cDNA libraries and identified several novel genes associated with prostate cancer, including SYT7, which they named IPCA7. IPCA7 expression was significantly associated with the expressions of the known prostate cancer-associated genes PSA (KLK3; 176820), PAP (ACPP; 171790), KLK2 (147960), MSMB (157145), and TGM4 (600585).
By in vitro characterization of recombinant rat Syt7, Li et al. (1995) determined that Syt7 showed Ca(2+)-dependent binding to phospholipids and Ca(2+)-independent binding to adaptor protein-2 (see 601026). Both C2 domains also showed Ca(2+)-dependent binding to syntaxins (see 186590).
Sugita et al. (2001) presented evidence that SYT7 functions as a plasma membrane Ca(2+) sensor in synaptic exocytosis. Alternatively spliced forms of rodent Syt7 were expressed in a developmentally regulated pattern in brain and were concentrated in presynaptic active zones of central synapses. In a rat neuroendocrine cell line, both C2 domains of Syt7 were potent inhibitors of Ca(2+)-dependent exocytosis, but only when they bound Ca(2+).
Shin et al. (2002) used gain-of-function C2-domain mutants of synaptotagmin-1 and loss-of-function C2-domain mutants of synaptotagmin-7 to examine how synaptotagmins function in dense-core vesicle exocytosis. Their data indicated that phospholipid, but not SNARE, binding by plasma membrane synaptotagmins is the primary determinant of calcium-triggered dense-core vesicle exocytosis. Shin et al. (2002) concluded that their results support a general lipid-based mechanism of action of synaptotagmins in exocytosis, with the specificity of various synaptotagmins for different types of fusion governed by their differential localizations and calcium affinities.
Chronic infection with the intracellular parasite Trypanosoma cruzi is prevalent in extensive areas of South and Central America. The parasite enters cells by a nonphagocytic mechanism. Entry requires mobilization of host cell lysosomes to the invasion site, as well as the triggering of a signaling cascade that results in localized elevation of free calcium. Thus, T. cruzi cell entry has several features resembling regulated exocytosis. By glass bead loading of cells with antibody to the C2A calcium-binding and exocytosis-regulating domain of SYT7, Caler et al. (2001) showed that T. cruzi, but not Toxoplasma gondii or Salmonella typhimurium, was markedly inhibited from entering the cells. Likewise, wildtype SYT7 C2A peptides but not those of other SYTs (e.g., SYT1; 185605) could block parasite entry. Caler et al. (2001) concluded that T. cruzi subverts the calcium-regulated lysosomal exocytic machinery involving the widely expressed SYT7 protein as a strategy for cell entry.
Roy et al. (2004) found that the lysosomal synaptotagmin SYT7 is required for a mechanism that promotes phagolysosomal fusion and limits the intracellular growth of pathogenic bacteria. SYT7 was required for a form of calcium-dependent phagolysosome fusion that is analogous to calcium-regulated exocytosis of lysosomes, which can be triggered by membrane injury. Bacterial type III secretion systems, which permeabilize membranes and cause calcium influx in mammalian cells, promote lysosomal exocytosis and inhibit intracellular survival in Syt7 wildtype but not null cells. Thus, the lysosomal repair response can also protect cells against pathogens that trigger membrane permeabilization.
Zhao et al. (2008) found that Syt7 was associated with lysosomes in mouse osteoclasts and with bone matrix protein-containing vesicles in mouse osteoblasts. Absence of Syt7 inhibited cathepsin K (CTSK; 601105) secretion and formation of the ruffled border in osteoclasts and bone matrix protein deposition in osteoblasts. Furthermore, Syt7-deficient mice were osteopenic due to impaired bone resorption and formation. Zhao et al. (2008) concluded that SYT7 is involved in bone remodeling and homeostasis by modulating secretory pathways in osteoclasts and osteoblasts.
Jackman et al. (2016) showed that SYT7 is a calcium sensor that is required for facilitation, a short-term form of enhancement in which each subsequent action potential evokes greater neurotransmitter release, at several central synapses. In Syt7-knockout mice, facilitation is eliminated even though the initial probability of release and the presynaptic residual calcium signals are unaltered. Expression of wildtype Syt7 in presynaptic neurons restored facilitation, whereas expression of a mutated Syt7 with a calcium-insensitive C2A domain did not. By revealing the role of SYT7 in synaptic facilitation, these results resolved a longstanding debate about a widespread form of short-term plasticity and enabled further studies of the functional importance of facilitation.
In mice, Turecek et al. (2017) found that Syt7, a calcium sensor for short-term facilitation, is present both at synapses from Purkinje cells to deep cerebellar nuclei and at vestibular synapses. Prolonged activation of these synapses leads to initial depression, which is followed by steady-state responses that are frequency-invariant for their physiologic activity range. At Purkinje cell and vestibular synapses, Syt7 supports facilitation that is normally masked by depression, which could be revealed in wildtype mice but was absent in Syt7 knockout mice. In wildtype mice, facilitation increased with firing frequency and counteracted depression to produce frequency-invariant transmission. In Syt7 knockout mice, Purkinje cell and vestibular synapses exhibited conventional use-dependent depression, weakening to a greater extent as the firing frequency was increased. Presynaptic rescue of Syt7 expression restored both facilitation and frequency-invariant transmission. Turecek et al. (2017) concluded that their results identified a function for Syt7 at synapses that exhibit overall depression, and demonstrated that facilitation has an unexpected and important function in producing frequency-invariant transmission.
Wu et al. (2017) showed that, in the pyramidal neurons of the hippocampal CA1 region in mice, blocking postsynaptic expression of both Syt1 and Syt7, but not of either alone, abolished long-term potentiation (LTP). LTP was restored by expression of wildtype Syt7 but not of a Ca(2+)-binding-deficient mutant Syt7. Blocking postsynaptic expression of Syt1 and Syt7 did not impair basal synaptic transmission, reduce levels of synaptic or extrasynaptic AMPA receptors, or alter other AMPA receptor trafficking events. Moreover, expression of dominant-negative mutant Syt1, which inhibits Ca(2+)-dependent presynaptic vesicle exocytosis, also blocked Ca(2+)-dependent postsynaptic AMPA receptor exocytosis, thereby abolishing LTP. Wu et al. (2017) concluded that their results suggested that postsynaptic Syt1 and Syt7 act as redundant Ca(2+) sensors for Ca(2+)-dependent exocytosis of AMPA receptors during LTP, and thereby delineated a simple mechanism for the recruitment of AMPA receptors that mediates LTP.
Maximov et al. (2008) found that homozygous Syt7-null mice were viable and fertile. Mutations in Syt7 that inactivated Ca(2+) binding to both C2 domains destabilized the protein, whereas inactivation of Ca(2+) binding to only the second C2 domain did not. Inhibitory neurons from Syt7-null mice were similar to wildtype neurons in synchronous and asynchronous neurotransmitter release and in presynaptic short-term plasticity. Maximov et al. (2008) concluded that Ca(2+) binding to SYT7 stabilizes the protein, but it does not regulate synaptic vesicle exocytosis.
Gustavsson et al. (2008) found that Syt7-null mice had impaired glucose-induced insulin secretion. Insulin sensitivity and production, pancreatic islet architecture and ultrastructural organization, and metabolic and calcium responses were normal in Syt7-null mice.
Loss of Syt1 abolishes fast exocytosis in chromaffin cells, but overall secretion is reduced by only 20% because slow exocytosis persists. Since Syt7 has the properties of a slow Ca(2+) sensor, with higher Ca(2+) affinity and slower binding kinetics than Syt1, Schonn et al. (2008) examined Ca(2+)-triggered exocytosis in chromaffin cells from Syt7-knockout mice and from knockin mice containing normal levels of a mutant Syt7 lacking the second Ca(2+)-binding domain. Both types of mutant chromaffin cells showed dramatically decreased Ca(2+)-triggered exocytosis. Moreover, in chromaffin cells lacking both Syt1 and Syt7, only a very slow release component persisted. Schonn et al. (2008) concluded that SYT7, together with SYT1, mediates almost all Ca(2+)-triggered exocytosis in chromaffin cells.
By transcript mapping of the 11q13 gene-rich region, Cooper et al. (1998) mapped the SYT7 gene to 11q13.
Caler, E. V., Chakrabarti, S., Fowler, K. T., Rao, S., Andrews, N. W. The exocytosis-regulatory protein synaptotagmin VII mediates cell invasion by Trypanosoma cruzi. J. Exp. Med. 193: 1097-1104, 2001. [PubMed: 11342594] [Full Text: https://doi.org/10.1084/jem.193.9.1097]
Cooper, P. R., Nowak, N. J., Higgins, M. J., Church, D. M., Shows, T. B. Transcript mapping of the human chromosome 11q12-q13.1 gene-rich region identifies several newly described conserved genes. Genomics 49: 419-429, 1998. [PubMed: 9615227] [Full Text: https://doi.org/10.1006/geno.1998.5291]
Fukuda, M., Ogata, Y., Saegusa, C., Kanno, E., Mikoshiba, K. Alternative splicing isoforms of synaptotagmin VII in the mouse, rat and human. Biochem. J. 365: 173-180, 2002. [PubMed: 12071850] [Full Text: https://doi.org/10.1042/BJ20011877]
Gustavsson, N., Lao, Y., Maximov, A., Chuang, J.-C., Kostromina, E., Repa, J. J., Li, C., Radda, G. K., Sudhof, T. C., Han, W. Impaired insulin secretion and glucose intolerance in synaptotagmin-7 null mutant mice. Proc. Nat. Acad. Sci. 105: 3992-3997, 2008. [PubMed: 18308938] [Full Text: https://doi.org/10.1073/pnas.0711700105]
Jackman, S. L., Turecek, J., Belinsky, J. E., Regehr, W. G. The calcium sensor synaptotagmin 7 is required for synaptic facilitation. Nature 529: 88-91, 2016. [PubMed: 26738595] [Full Text: https://doi.org/10.1038/nature16507]
Li, C., Ullrich, B., Zhang, J. Z., Anderson, R. G. W., Brose, N., Sudhof, T. C. Ca(2+)-dependent and -independent activities of neural and non-neural synaptotagmins. Nature 375: 594-599, 1995. [PubMed: 7791877] [Full Text: https://doi.org/10.1038/375594a0]
Maximov, A., Lao, Y., Li, H., Chen, X., Rizo, J., Sorensen, J. B., Sudhof, T. C. Genetic analysis of synaptotagmin-7 function in synaptic vesicle exocytosis. Proc. Nat. Acad. Sci. 105: 3986-3991, 2008. [PubMed: 18308933] [Full Text: https://doi.org/10.1073/pnas.0712372105]
Roy, D., Liston, D. R., Idone, V. J., Di, A., Nelson, D. J., Pujol, C., Bliska, J. B., Chakrabarti, S., Andrews, N. W. A process for controlling intracellular bacterial infections induced by membrane injury. Science 304: 1515-1518, 2004. [PubMed: 15178804] [Full Text: https://doi.org/10.1126/science.1098371]
Schonn, J.-S., Maximov, A., Lao, Y., Sudhof, T. C., Sorensen, J. B. Synaptotagmin-1 and -7 are functionally overlapping Ca(2+) sensors for exocytosis in adrenal chromaffin cells. Proc. Nat. Acad. Sci. 105: 3998-4003, 2008. [PubMed: 18308932] [Full Text: https://doi.org/10.1073/pnas.0712373105]
Shin, O.-H., Rizo, J., Sudhof, T. C. Synaptotagmin function in dense core vesicle exocytosis studied in cracked PC12 cells. Nature Neurosci. 5: 649-656, 2002. [PubMed: 12055633] [Full Text: https://doi.org/10.1038/nn869]
Sugita, S., Han, W., Butz, S., Liu, X., Fernandez-Chacon, R., Lao, Y., Sudhof, T. C. Synaptotagmin VII as a plasma membrane Ca(2+) sensor in exocytosis. Neuron 30: 459-473, 2001. [PubMed: 11395007] [Full Text: https://doi.org/10.1016/s0896-6273(01)00290-2]
Turecek, J., Jackman, S. L., Regehr, W. G. Synaptotagmin 7 confers frequency invariance onto specialized depressing synapses. Nature 551: 503-506, 2017. [PubMed: 29088700] [Full Text: https://doi.org/10.1038/nature24474]
Walker, M. G., Volkmuth, W., Sprinzak, E., Hodgson, D., Klingler, T. Prediction of gene function by genome-scale expression analysis: prostate cancer-associated genes. Genome Res. 9: 1198-1203, 1999. [PubMed: 10613842] [Full Text: https://doi.org/10.1101/gr.9.12.1198]
Wu, D., Bacaj, T., Morishita, W., Goswami, D., Arendt, KL., Xu, W., Chen, L., Malenka, R. C., Sudhof, T. C. Postsynaptic synaptotagmins mediate AMPA receptor exocytosis during LTP. Nature 544: 316-321, 2017. [PubMed: 28355182] [Full Text: https://doi.org/10.1038/nature21720]
Zhao, H., Ito, Y., Chappel, J., Andrews, N. W., Teitelbaum, S. L., Ross, F. P. Synaptotagmin VII regulates bone remodeling by modulating osteoclast and osteoblast secretion. Dev. Cell 14: 914-925, 2008. [PubMed: 18539119] [Full Text: https://doi.org/10.1016/j.devcel.2008.03.022]