Disease relevance of Syt4

• In the human neuroblastoma cell line SK-N-SH, SYT IV is an immediate-early gene inducible by elevated intracellular calcium and by forskolin, an activator of adenylyl cyclase [1].
• Together, these data suggest that neural activity during singing can drive Syt IV expression within song circuitry whereas generalized seizure activity fails to do so even though song control areas are depolarized [2].

Psychiatry related information on Syt4

• These results suggest that Syt IV is required in certain types of neurons for optimal functionality, that perturbations in the levels of Syt IV can result in memory loss in mice, and that Syt IV alterations may lead to psychiatric disease in humans [3].

High impact information on Syt4

• Synaptotagmin IV regulates glial glutamate release [4].
• Within brain, human SYT IV mRNA is most highly expressed in hippocampus, with lower levels present in amygdala and thalamus [1].
• Rat synaptotagmin IV (SYT IV) is a depolarization-inducible synaptic vesicle protein [1].
• The human SYT IV gene maps to chromosome band 18q12.3, a region that defines a break point in the synteny with mouse chromosome 18 and has been implicated by associated markers in two human psychiatric disorders [1].
• The human synaptotagmin IV gene defines an evolutionary break point between syntenic mouse and human chromosome regions but retains ligand inducibility and tissue specificity [1].

Biological context of Syt4

• The predicted amino acid sequence of the human SYT IV clone is nearly 90% identical to the rat and mouse SYT IV proteins [1].
• To test this hypothesis in neurons of the mammalian CNS, we measured field excitatory postsynaptic potentials (fEPSPs) in hippocampal slice preparations from Syt IV (-/-) mice [5].
• Expression of one such cDNA, which exhibited 98% sequence homology with the synaptic vesicle protein synaptotagmin IV, decreased 2 h after MDMA treatment [6].
• MDMA did not induce down- or up-regulation of synaptotagmin IV and I, respectively, in serotonin transporter knockout mice (-/-) that are not sensitive to MDMA [6].
• Synaptotagmin IV: biochemistry, genetics, behavior, and possible links to human psychiatric disease [3].

Anatomical context of Syt4

• Synaptotagmin IV (Syt IV) is an activity-inducible, secretory vesicle protein that is thought to function as an inhibitor of neurotransmitter release (Littleton et al. Nature 400:757-760, 1999) [5].
• As judged by immunohistochemical criteria, the synaptic structure and connectivity of the hippocampus and raphe nucleus in Syt IV (-/-) mice are indistinguishable from wild-type littermates [7].
• PCR analyses (semi-quantitative and real-time) confirmed that upon treatment with MDMA, expression of synaptotagmin IV decreased both in the midbrain and frontal cortex of mice [6].
• Experimental perturbation of Syt IV modulates neurotransmitter release in mice, flies, and PC12 cells, and modulates learning in mice [2].
• In cultures, immunocytochemical analysis has shown that Syt IV is localized at the Golgi and at the tips of growing neurites, but little was known about associations between Syt IV and vesicles or organelles [J. Neurochem. 74 (2000) 518] [8].

Associations of Syt4 with chemical compounds

• The Ca2+-dependent interaction of the C2A domain of synaptotagmin IV with PS was found to have two components with EC50 values of approximately 5 and 120 microM free Ca2+ and exhibited positive cooperativity (Hill coefficient of approximately 2 for both components) [9].
• In addition, the C2A domain of synaptotagmin IV cannot bind liposomes consisting of PS (or PI) and phosphatidylcholine, PC (or phosphatidylethanolamine, PE) (1:1, w/w), indicating that the binding to negatively charged phospholipids is inhibited by the presence of PC or PE [9].
• Mutational analysis indicated that this phospholipid composition-dependent Ca2+ binding of synaptotagmin IV results in the substitution of Asp for Ser at position 244 [9].
• In addition, human SYT IV has a characteristic serine for aspartate substitution within the first C2 domain that is conserved among Drosophila, Caenorhabditis elegans, mouse, and rat SYT IV sequences [1].

Analytical, diagnostic and therapeutic context of Syt4

• Because Syt IV and abnormalities in neurotransmission have been implicated in psychiatric disease, we examined Syt IV (-/-) mice in animal models of mood-related behavior [7].
• Decreases in the protein levels of synaptotagmin IV were confirmed by Western immunoblotting with anti-synaptotagmin IV antibodies [6].
• Synaptotagmin IV (Syt IV) expression is regulated by neuronal development and by depolarization in the brain and in neuronal cell cultures [8].
• Some Syt IV signals were clearly associated with vesicles and/or organelles, but EM and cell fractionation studies showed no Syt IV signals at synaptic vesicles [8].

References