Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.5 (thrombin)
 33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Serine proteases exert a variety of functions in the body; food digestion, regulation of other proteins and modification of extracellular matrix. Cumulative evidence has shown the importance of serine proteases in the nervous system as well. It has been shown that three serine proteases, thrombin, plasminogen activators and neuropsin, have functional roles in neural plasticity. Most of the actions of thrombin are thought to be mediated by its specific receptors. Thrombin reverses neurite outgrowth of serum-deprived neuroblastoma cells, and induces protective and apoptotic effects on neurons and glial cells depending on concentration and time. Tissue-type and urokinase-type plasminogen activators (tPA and uPA) distribute broadly in the brain. tPA and uPA exert a variety of functions during development. These proteases also function in long-term potentiation and kindling formation. Furthermore, tPA is essential to excitotoxic neuronal cell death. Neuropsin is a serine protease expressed in the limbic system of the brain. Kindling induced neuropsin mRNA and protein expression and anti-neuropsin antibody ameliorates kindling epilepsy. The possible roles of these proteases in neural plasticity are reviewed here.
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PMID:Plasticity-related serine proteases in the brain (review). 1008 14

Serine proteases are involved in many processes in the nervous system and specific inhibitors tightly control their proteolytic activity. Thrombin is thought to play a role in tissue development and homeostasis. To date, protease nexin-1 is the only known endogenous protease inhibitor that specifically interferes with thrombotic activity and is expressed in the brain. In this study, we report the detection of a novel thrombin inhibitory activity in the brain of protease nexin-1(-/-) mice. Purification and subsequent analysis by tandem mass spectrometry identified this protein as the phosphatidylethanolamine-binding protein (PEBP). We demonstrate that PEBP exerts inhibitory activity against several serine proteases including thrombin, neuropsin, and chymotrypsin, whereas trypsin, tissue type plasminogen activator, and elastase are not affected. Since PEBP does not share significant homology with other serine protease inhibitors, our results define it as the prototype of a novel class of serine protease inhibitors. PEBP immunoreactivity is found on the surface of Rat-1 fibroblast cells and although its sequence contains no secretion signal, PEBP-H(6) can be purified from the conditioned medium upon recombinant expression.
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PMID:The phosphatidylethanolamine-binding protein is the prototype of a novel family of serine protease inhibitors. 1103 91

Much attention has been paid to proteases involved in long-term potentiation (LTP). Calpains, Ca-dependent cysteine proteases, have first been demonstrated to be the mediator of LTP by the proteolytic cleavage of fodrin, which allows glutamate receptors located deep in the postsynaptic membrane to move to the surface. It is now generally considered that calpain activation is necessary for LTP formation in the cleavage of substrates such as protein kinase Czeta, NMDA receptors, and the glutamate receptor-interacting protein. Recent studies have shown that serine proteases such as tissue-type plasminogen activator (tPA), thrombin, and neuropsin are involved in LTP. tPA contributes to LTP by both receptor-mediated activation of cAMP-dependent protein kinase and the cleavage of NMDA receptors. Thrombin induces a proteolytic activation of PAR-1, resulting in activation of protein kinase C, which reduces the voltage-dependent Mg2+ blockade of NMDA receptor-channels. On the other hand, neuropsin may act as a regulatory molecule in LTP via its proteolytic degradation of extracellular matrix protein such as fibronectin. In addition to such neuronal proteases, proteases secreted from microglia such as tPA may also contribute to LTP. The enzymatic activity of each protease is strictly regulated by endogenous inhibitors and other factors in the brain. Once activated, proteases can irreversibly cleave peptide bonds. After cleavage, some substrates are inactivated and others are activated to gain new functions. Therefore, the issue to identify substrates for each protease is very important to understand the molecular basis of LTP.
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PMID:Proteases involved in long-term potentiation. 1246 76

The phosphatidylethanolamine-binding protein (PEBP) family is widely distributed in various species, from bacteria to mammals. These proteins seem to modulate important cell mechanisms: they control heterotrimeric G-proteins, inhibit the MAP-kinase and NFkappaB signaling pathways, and also serine proteases (thrombin, neuropsin, and chymotrypsin). In order to establish structure-function relationships for this family of proteins, our study focuses on PEBPs expressed within a single organism: Drosophila melanogaster, which constitutes a model system that lends itself well to establishing links between genes' expression and the corresponding proteins' functions, and to studying physiological mechanisms such as development. Here, we describe an optimized protocol for high level over-expression and high yield/high purity production of CG18594, one of Drosophila six putative PEBPs, for biophysical studies. The yield of the purified 15N labeled protein is estimated to be 60 mg/L of M9 minimal medium. Analysis of the secondary structure using circular dichroism indicates that the protein comprises mainly beta-sheets at pH 7. The good dispersion of the crosspeaks on the 1H-15N HSQC spectrum provides evidence of a proper folding of the purified protein, though its time evolution suggests a tendency to denature. Taken together, these data are consistent with the assumption that the CG18594 protein belongs to the PEPB family.
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PMID:Cloning, high yield over-expression, purification, and characterization of CG18594, a new PEBP/RKIP family member from Drosophila melanogaster. 1652 46

Serine proteases such as tissue plasminogen activator (tPA), thrombin and neuropsin influence hippocampal plasticity involved in learning and memory by facilitating both synaptic remodelling and long-term potentiation. Given our previous findings that trypsin and its receptor, protease-activated receptor-2 (PAR2), are both highly expressed in pyramidal neurons of the hippocampus and that activation of PAR2 attenuates 'pathogenic' plasticity related to epilepsy, we wished to determine the role for PAR2 in normal, non-pathological hippocampal plasticity related to learning and memory. In a strain of rat that show high basal levels of anxiety, the Genetic Absence Epilepsy Rats from Strasbourg (GAERS), peripheral administration of the PAR2 peptide agonist, SLIGRL (1.5 mg/kg s.c.), induced distinct deficits in experience-dependent learning both in the test-retest paradigm of the elevated-plus maze and in the Morris water maze. In separate, conscious rats with indwelling intra-cerebroventricular cannulae, SLIGRL rapidly appeared in cerebrospinal fluid (CSF) following peripheral administration and had a half-life in CSF of approximately 25 min. These results suggest that activation of central PAR2 with brain accessible peptide agonists causes a temporary deficit in the formation and/or recollection of experience-dependent learning and memory.
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PMID:A regulatory role for protease-activated receptor-2 in motivational learning in rats. 1941 9

Recent studies implicate extracellular proteases in synaptic plasticity, learning, and memory. The data are especially strong for such serine proteases as thrombin, tissue plasminogen activator, neurotrypsin, and neuropsin as well as matrix metalloproteinases, MMP-9 in particular. The role of those enzymes in the aforementioned phenomena is supported by the experimental results on the expression patterns (at the gene expression and protein and enzymatic activity levels) and functional studies, including knockout mice, specific inhibitors, etc. Counterintuitively, the studies have shown that the extracellular proteolysis is not responsible mainly for an overall degradation of the extracellular matrix (ECM) and loosening perisynaptic structures, but rather allows for releasing signaling molecules from the ECM, transsynaptic proteins, and latent form of growth factors. Notably, there are also indications implying those enzymes in the major neuropsychiatric disorders, probably by contributing to synaptic aberrations underlying such diseases as schizophrenia, bipolar, autism spectrum disorders, and drug addiction.
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PMID:Neural ECM proteases in learning and synaptic plasticity. 2541 Mar 56