Disease relevance of Syt4

• Synaptotagmin IV (SytIV), an immediate-early gene induced by depolarization in PC12 pheochromocytoma cells and in the hippocampus, has been suggested to work as a negative regulator of neurotransmitter release [1].

High impact information on Syt4

• Overexpression of synaptotagmin I prolonged the time from fusion pore opening to dilation, whereas synaptotagmin IV shortened this time [2].
• The first C2 domains of synaptotagmins I-III exhibit similar Ca2+ affinities in phospholipid-binding assays, whereas that of synaptotagmin IV is unable to bind Ca2+ [3].
• SytIV mRNA accumulation is transiently induced in PC12 cells by potassium depolarization, calcium ionophore, ATP, and forskolin [4].
• Kainic acid-induced seizures in rats are followed by accumulation of SytIV message in the hippocampus and piriform cortex [4].
• The SytIV gene may provide a direct link between depolarization-induced neuronal gene expression and subsequent modulation of synaptic structure and function [4].

Biological context of Syt4

• Synaptotagmin IV is an immediate early gene induced by depolarization in PC12 cells and in brain [4].
• Our results suggest that Syt IV is a stimulus (e.g. NGF)-dependent regulator for exocytosis of dense-core vesicles [5].
• Effect of forskolin on synaptotagmin IV protein trafficking in PC12 cells [6].
• The dominant hypothesis of Syt IV function states that Syt IV upregulation is a neuroprotective mechanism for reducing neurotransmitter release [7].
• Synaptotagmin IV does not alter excitatory fast synaptic transmission or fusion pore kinetics in mammalian CNS neurons [7].

Anatomical context of Syt4

• Syt4, the fourth identified member of the synaptotagmin family, is inducible in PC12 cells by depolarization and secretagogues, and in limbic regions of the adult rat brain by kainic acid-induced seizures [8].
• However, the involvement of Syt IV protein in vesicular trafficking and even its localization in secretory vesicles are still matters of controversy [5].
• By contrast, limited colocalization of Syt IV protein with dense-core vesicle markers is found in the distal parts of the neurites of NGF-differentiated PC12 cells [5].
• Heterogeneous sets of neurons expressing synaptotagmin IV gene also were observed in spinal cord [9].
• Furthermore, synaptotagmin IV was seen in the proximal part of the growth cone domain and not in the microfilament-rich region which includes filopodia [10].

Associations of Syt4 with chemical compounds

• Sucrose density gradient fractionation and vesicle immunoisolation experiments suggest that Syt IV protein is present in both synaptic-like microvesicles and secretory granules [11].
• However, conversion of the unique serine in SytIV to an aspartate eliminated this inhibitory activity [1].
• Unlike other synaptotagmins, SytIV has an evolutionarily conserved substitution of an aspartate to a serine in the Ca(2+) coordination site of its C2A domain, preventing SytIV from binding anionic lipids in a Ca(2+)-dependent fashion [1].
• We have examined the pattern of expression of Syt IV mRNA following the administration of cocaine and amphetamine [12].
• Effect of acute and chronic treatment with methamphetamine on mRNA expression of synaptotagmin IV and 25 KDa-synaptic-associated protein in the rat brain [13].

Other interactions of Syt4

• In the present study, we examined the time course of the seizure-induced changes in the expression of Syt4 and Syt1, both in adult animals and during the postnatal period [8].
• Synaptotagmin III is about 10 times greater in the neural tissues versus the pituitary, and synaptotagmin IV was the least abundant isoform in all the tissues [14].
• We further characterized the expression of two genes linked to neurogenesis (nestin and stathmin), and two genes likely involved in reconfiguring neuronal networks (semaphorin VIa and synaptotagmin IV) [15].
• These included furin, prosaposin, synaptotagmin IV, heat shock protein 105, and the neutral and basic amino acid transporter (NBAT) [16].

Analytical, diagnostic and therapeutic context of Syt4

• (ii) Immunoelectron microscopy with highly specific anti-Syt IV antibody revealed that the Syt IV protein in undifferentiated PC12 cells is mainly present on the Golgi membranes and immature secretory vesicles, whereas after NGF stimulation Syt IV protein is also present on the mature dense-core vesicles [5].
• Crystallography reveals that changes in the orientations of critical Ca(2+) ligands, and perhaps their flexibility, render the rat synaptotagmin 4 C(2)B domain unable to form full Ca(2+)-binding sites [17].
• These results indicate that synaptotagmin 4 is a Ca(2+) sensor in the fly but not in the rat, that the Ca(2+)-binding properties of C(2) domains cannot be reliably predicted from sequence analyses, and that proteins clearly identified as orthologs may nevertheless have markedly different functional properties [17].
• The 46-kDa Syt IV protein is nearly undetectable by western blotting in unstimulated PC12 cells [11].
• The rate of Syt IV protein synthesis, determined by labeling with radioactive amino acids and immunoprecipitation, is low in unstimulated PC12 cells, but increases over the first 3 h after forskolin stimulation and remains elevated for several hours [11].

References