HGNC Approved Gene Symbol: SYT3
Cytogenetic location: 19q13.33 Genomic coordinates (GRCh38): 19:50,621,977-50,658,105 (from NCBI)
Synaptotagmin-1 (SYT1; 185605), an integral membrane protein of synaptic vesicles, is thought to be involved in calcium-dependent exocytosis of synaptic vesicles. Mizuta et al. (1994) cloned a novel isoform of synaptotagmin, designated synaptotagmin-3, from a rat brain cDNA library and studied its tissue distribution. The protein contains 588 amino acids having 40.5, 38.3, and 64.0% identity with rat synaptotagmin-1, rat synaptotagmin-2 (SYT2; 600104), and a third synaptotagmin isoform of the marine ray, respectively. The region of the 2 internal repeats homologous to the regulatory domain of protein kinase C was highly conserved among the 3 synaptotagmins. RNA blot studies demonstrated that synaptotagmin-3 mRNA is expressed in brain, various endocrine tissues, and hormone-secreting clonal cells. It appeared to be involved in Ca(2+)-dependent exocytosis of secretory vesicles in endocrine cells, as well as in neurons.
By in vitro characterization of recombinant rat Syt3, Li et al. (1995) determined that Syt3 showed Ca(2+)-dependent binding to phospholipids, Ca(2+)-dependent binding to syntaxins (see 186590), and Ca(2+)-independent binding to adaptor protein-2 (see 601026).
Awasthi et al. (2019) discovered that Syt3 localizes to postsynaptic endocytic zones and removes AMPA receptors from synaptic plasma membranes in response to stimulation. AMPA receptor internalization, long-term depression (LTD), and decay of long-term potentiation (LTP) of synaptic strength required calcium-sensing by Syt3 and were abolished through Syt3 knockout. In spatial memory tasks, mice in which Syt3 was knocked out learned normally but exhibited a lack of forgetting. Disrupting Syt3:GluA2 (GRIA2; 138247) binding in a wildtype background mimicked the lack of LTP decay and lack of forgetting, and these effects were occluded in the Syt3 knockout background. Awasthi et al. (2019) concluded that their findings provided evidence for a molecular mechanism in which Syt3 internalizes AMPA receptors to depress synaptic strength and promote forgetting.
Using an interspecific backcross DNA panel, Jones et al. (1995) demonstrated that the mouse Syt3 gene is located on mouse chromosome 7; no recombinants were observed between Syt3 and the kallikrein gene family (Kal) in 94 meioses. To map human SYT3, they probed a Southern blot containing genomic DNAs from a somatic cell mapping panel and found segregation with chromosome 19. Thus, SYT3 appears to be located in the conserved linkage group on proximal mouse chromosome 7 and human chromosome 19q that is known to include at least 28 genes (Holdener et al., 1993). Kwon et al. (1995) likewise mapped Syt3 to mouse chromosome 7.
Awasthi, A., Ramachandran, B., Ahmed, S., Benito, E., Shinoda, Y., Nitzan, N., Heukamp, A., Rannio, S., Martens, H., Barth, J., Burk, K., Wang, Y. T., Fischer, A., Dean, C. Synaptotagmin-3 drives AMPA receptor endocytosis, depression of synapse strength, and forgetting. Science 363: eaav1483, 2019. Note: Electronic Article. [PubMed: 30545844] [Full Text: https://doi.org/10.1126/science.aav1483]
Holdener, B. C., Brown, S. D. M., Angel, J. M., Nicholls, R. D., Kelsey, G., Magnuson, T. Mouse chromosome 7. Mammalian Genome 4 (suppl.): S110-S120, 1993. [PubMed: 8268667] [Full Text: https://doi.org/10.1007/BF00360833]
Jones, J. M., Popma, S. J., Mizuta, M., Seino, S., Meisler, M. H. Synaptotagmin genes on mouse chromosomes 1, 7, and 10 and human chromosome 19. Mammalian Genome 6: 212-213, 1995. [PubMed: 7749232] [Full Text: https://doi.org/10.1007/BF00293017]
Kwon, O.-J., Adamson, M. C., Chin, H., Kozak, C. A. Genetic mapping of five mouse genes encoding synaptotagmins. Mammalian Genome 6: 880-881, 1995. [PubMed: 8747928] [Full Text: https://doi.org/10.1007/BF00292439]
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]
Mizuta, M., Inagaki, N., Nemoto, Y., Matsukura, S., Takahashi, M., Seino, S. Synaptotagmin III is a novel isoform of rat synaptotagmin expressed in endocrine and neuronal cells. J. Biol. Chem. 269: 11675-11678, 1994. [PubMed: 8163462]