The transglutaminase hypothesis for the action of tetanus toxin

doi:10.1016/0968-0004(93)90066-V

Trends in Biochemical Sciences

Volume 18, Issue 9, September 1993, Pages 327-329

https://doi.org/10.1016/0968-0004(93)90066-V Get rights and content

Abstract

Tetanus toxin potently and almost irreversibly inhibits the release of neurotransmitters from nerve terminals. The toxin binds to and activates transglutaminase, a Ca²⁺-dependent enzyme that can form stable crosslinks between substrate proteins. Transglutaminase is present in nerve terminals and recognizes synapsin I, an abundant synaptic vesicle phosphoprotein involved in neurotransmission, as an excellent substrate. The neuroparalytic action of tetanus toxin might be due, at least in part, to the stimulation of synaptic transglutaminase and the consequent crosslinking of synapsin I.

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Cited by (33)

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Molecular network and chromosomal clustering of genes involved in synaptic plasticity in the hippocampus
2006, Journal of Biological Chemistry
Citation Excerpt :
In the nervous system, a variety of regulatory activities of transglutaminases has been suggested. These include stabilization of synapses, synapse formation and differentiation, neurotransmitter release, and modulation of adenylyl cyclase and CREB activation (54-58). To examine if the transglutaminase is involved in the regulation of LTP, we determined the effect of cystamine, a specific antagonist of the enzyme (59, 60), on LTP expression.
Gene transcription is required for establishing and maintaining the enduring form of long term potentiation (LTP). However, the transcriptome and its associated molecular programs that support LTP are not well understood. The purpose of this study was to identify activity-regulated genes (ARGs) and their molecular pathways that are modulated by LTP induction and to investigate the genomic mechanism for coordinating the transcription of ARGs. We performed time course DNA microarray analyses on the mouse dentate gyrus to determine the temporal genomic expression profiles of ARGs in response to LTP-inducing tetanic stimulation. Our studies uncovered ARGs that regulate various cellular processes, including the structure and function of the synapse, and offered an overview of the dynamic molecular programs that are probably important for LTP. Surprisingly, we found that ARGs are clustered on chromosomes, and ARG clusters are conserved during evolution. Although ARGs in the same cluster have apparently different molecular properties, they are functionally correlated by regulating LTP. In addition, ARGs in specific clusters are co-regulated by the cAMP-response element-binding protein. We propose that chromosomal clustering provides a genomic mechanism for coordinating the transcription of ARGs involved in LTP.
A tetanus toxin sensitive protein other than VAMP 2 is required for exocytosis in the pancreatic acinar cell
2000, FEBS Letters
The neurotoxin sensitivity of regulated exocytosis in the pancreatic acinar cell was investigated using streptolysin-O permeabilized pancreatic acini. Treatment of permeabilized acini with botulinum toxin B (BoNT/B) or botulinum toxin D (BoNT/D) had no detectable effect on Ca²⁺-dependent amylase secretion but did result in the complete cleavage of VAMP 2. In comparison, tetanus toxin (TeTx) treatment both significantly inhibited Ca²⁺-dependent amylase secretion and cleaved VAMP 2. These results indicate that regulated exocytosis in the pancreatic acinar cell requires a tetanus toxin sensitive protein(s) other than VAMP 2.
Activation of signal transduction pathways involving trkA, PLCγ-1, PKC isoforms and ERK-1/2 by tetanus toxin
2000, FEBS Letters
Previous reports have demonstrated that tetanus toxin (TeTx) induces activation and down-regulation of protein kinase C (PKC). In the present work the differential activation of PKC isoforms and of signal transduction pathways, including nerve growth factor receptor trkA, phospholipase Cγ-1 (PLCγ-1), and extracellular regulated kinases 1 and 2 (ERK-1/2) by TeTx in a synaptosome-enriched P₂ fraction from rat brain is reported. TeTx induces clear translocation from the soluble (cytosolic) compartment to the particulate (membranous) compartment of PKC-β, -γ and -δ isoforms, whereas PKC-ϵ showed a slight decrease of its soluble fraction immunoreactivity. On the contrary, the PKC-ζ isoform shows no consistent response, whereas down-regulation of total PKC-α immunoreactivity is shown. Immunoprecipitation assays against phosphotyrosine show an increase of trkA and PLCγ-1 phosphorylation. Moreover, trkA activation is corroborated using phospho-specific antibodies against phosphorylated trkA. On the other hand, TeTx-induced stimulation of mitogen-activated protein (MAP) kinase activity is observed, this event also being detected by Western analysis using phospho-specific antibodies against ERK-1/2.
Colocalization of tissue transglutaminase and stress fibers in human vascular smooth muscle cells and human umbilical vein endothelial cells
1997, Experimental Cell Research
The subcellular distribution of tissue transglutaminase in human umbilical vein endothelial cells and human arterial and venous smooth muscle cells was examined. Double-immunofluorescence staining of smooth muscle cells and endothelial cells with anti-transglutaminase antisera and rhodamine-tagged phalloidin revealed codistribution of transglutaminase with the stress fibers, with endothelial cells also containing a cytoplasmic pool. This pattern of distribution was confirmed by confocal microscopy. Immunoprecipitation experiments demonstrated that transglutaminase co-immunoprecipitated with myosin in high-molecular-weight complexes, but not with actin, suggesting that the association of transglutaminase with the stress fibers was due to its cross-linking to myosin. About 97% of endothelial cell transglutaminase activity was present in the cytosolic fraction and 3% in the particulate fraction. The detergent-insoluble fraction was practically devoid of activity as measured by the putrescine assay, but was active as evidenced by the covalent cross-linking of¹²⁵I-fibronectin. Western blotting with a polyclonal rabbit antiserum raised against human erythrocyte transglutaminase detected high levels of enzyme in endothelial cell cytosol and both detergent-soluble and detergent-insoluble membrane fractions. In contrast, smooth muscle cells contained much less cytosolic transglutaminase, as determined either functionally or antigenically. Furthermore, within the particulate fraction of the smooth muscle cells, most of the enzyme was located in the detergent-insoluble fraction, as assessed by Western blot analysis. Retinoic acid increased the levels of enzyme in the cytosol of all cell types and the increases were correlated with increases in mRNA. Thus, tissue transglutaminase is present in various particulate fractions of vascular smooth muscle cells and endothelial cells and may be present in this cellular fraction by virtue of autocross-linking of the enzyme itself to stress fiber-associated myosin.
Expression of GTP-dependent and GTP-independent tissue-type transglutaminase in cytokine-treated rat brain astrocytes
1997, Journal of Biological Chemistry
Tissue-type transglutaminases (TGases) were recently shown to exert dual enzymatic activities; they catalyze the posttranslational modification of proteins by transamidation, and they also act as guanosine triphosphatase (GTPase). Here we show that a tissue-type TGase is expressed in rat brain astrocytes in vitro, and is induced by the inflammation-associated cytokines interleukin-1β and to a lesser extent by tumor necrosis factor-α. Induction is accompanied by overexpression and appearance of an additional shorter clone, which does not contain the long 3′-untranslated region and encodes for a novel TGase enzyme whose C terminus lacks a site that affects the enzyme's interaction with guanosine triphosphate (GTP). Expression of two clones revealed that the long form is inhibited noncompetitively by GTP, but the short form significantly less so. The different affinities for GTP may account for the difference in physiological function between these two enzymes.

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Trends in Biochemical Sciences

The transglutaminase hypothesis for the action of tetanus toxin

Abstract

FEBS Lett.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Exp. Cell Res.

Biochim. Biophys. Acta

Neuroscience

Annu. Rev. Pharmacol. Toxicol.

Nature

J. Neurochem.

Tetanus

Molecular network and chromosomal clustering of genes involved in synaptic plasticity in the hippocampus

A tetanus toxin sensitive protein other than VAMP 2 is required for exocytosis in the pancreatic acinar cell

Activation of signal transduction pathways involving trkA, PLCγ-1, PKC isoforms and ERK-1/2 by tetanus toxin

Colocalization of tissue transglutaminase and stress fibers in human vascular smooth muscle cells and human umbilical vein endothelial cells

Expression of GTP-dependent and GTP-independent tissue-type transglutaminase in cytokine-treated rat brain astrocytes