Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.6.4 (chondroitinase)
2,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PTP zeta is a receptor-type protein-tyrosine phosphatase that is synthesized as a chondroitin sulfate proteoglycan and uses pleiotrophin as a ligand. The chondroitin sulfate portion of this receptor is essential for high affinity binding to pleiotrophin. Here, we purified phosphacan, which corresponds to the extracellular domain of PTP zeta, from postnatal day 7 (P7) and P12 rat cerebral cortex (PG-P7 and PG-P12, respectively) and from P20 rat whole brain (PG-P20). The chondroitin sulfate of these preparations displayed immunologically and compositionally different structures. In particular, only PG-P20 reacted with the monoclonal antibody MO-225, which recognizes chondroitin sulfate containing the GlcA(2S)beta 1-3GalNAc(6S) disaccharide unit (D unit). Analysis of the chondroitinase digestion products revealed that GlcA beta 1-3GalNAc(4S) disaccharide unit (A unit) was the major component in these preparations and that PG-P20 contained 1.3% D unit, which was not detected in PG-P7 and PG-P12. Interaction analysis using a surface plasmon resonance biosensor indicated that PG-P20 had approximately 5-fold stronger affinity for pleiotrophin (dissociation constant (KD) = 0.14 nM) than PG-P7 and PG-P12, although all these preparations showed similar low affinity binding to pleiotrophin after chondroitinase ABC digestion (KD = 1.4 approximately 1.6 nM). We also found that shark cartilage chondroitin sulfate D containing approximately 20% D unit bound to pleiotrophin with moderate affinity (KD = 2.7 nM), whereas whale cartilage chondroitin sulfate A showed no binding to this growth factor. These results suggest that variation of chondroitin sulfate plays important roles in the regulation of signal transduction in the brain.
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PMID:Heterogeneity of the chondroitin sulfate portion of phosphacan/6B4 proteoglycan regulates its binding affinity for pleiotrophin/heparin binding growth-associated molecule. 1284 14

Cell bodies and their dendrites of motor neurons, motor-related neurons, and certain other subsets of neurons such as GABAergic interneurons in the mature brain and spinal cord possess intensely negatively charged perineuronal or perisynaptic nets of proteoglycans which are linked to the nerve cell surface glycoproteins. These perineuronal nets of proteoglycans are digested by chondroitinase ABC, hyaluronidase, or collagenase, but not by endo-alpha-N-acetylgalactosaminidase, which is reactive to the nerve cell surface glycoproteins. Aggrecan, versican, neurocan, and brevican are members of a family of chondroitin sulfate proteoglycans that bind to hyaluronan. Neurocan- or brevican-deficient mice showed a regionally heterogeneous composition of proteoglycans in perineuronal nets. Aggrecan glycoforms contribute to the molecular heterogeneity of the perineuronal nets. Proteoglycans such as phosphacan are included in matrix-associated proteoglycans. The extracellular matrix glycoprotein tenascin-R is accumulated in the perineuronal nets. The perineuronal proteoglycans are produced by associated satellite astrocytes just before weaning, while the nerve cell surface glycoproteins are produced by the associated nerve cells at earlier stages after birth. The perineuronal proteoglycans may entrap the tissue fluid and form a perineuronal gel layer which protects the synapses as a "perisynaptic barrier". Degradation of the perineuronal proteoglycans or perisynaptic barrier by treatment with chondroitinase ABC or hyaluronidase reactivates the neuronal plasticity or promotes the functional recovery of a severed nervous system. Another set of perineuronal nets occurs, which are intensely positively charged and contain guanidino compounds. It is considered that these intensely positively charged nets are intermingled with the intensely negatively charged ones of proteoglycans.
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PMID:Perisynaptic barrier of proteoglycans in the mature brain and spinal cord. 1452 61

Neuroglycan C (NGC), a brain-specific transmembrane proteoglycan, is thought to bear not only chondroitin sulfate but also N- and O-linked oligosaccharides on its core protein. In this study, we isolated and purified NGC from rat brains at various developmental stages by immunoaffinity column chromatography or by immunoprecipitation, and examined the structural characters of its carbohydrate moiety. The chondroitin sulfate disaccharide composition of NGC at postnatal day 10 was significantly different from those of two secreted chondroitin sulfate proteoglycans, neurocan and phosphacan, purified from the brain at the same developmental stage; higher levels of 4-sulfate unit and E unit, a disulfated disaccharide unit, and a lower level of 6-sulfate unit. The levels of both 6-sulfate and E units decreased with a compensatory increase of 4-sulfate unit with postnatal development of the brain. Lectin-blot analysis of the NGC core glycoprotein prepared by chondroitinase digestion confirmed that NGC actually bore both N- and O-linked carbohydrates, and also revealed that lectin-species reactive with NGC did not always recognize other brain-specific proteoglycans, neurocan and phosphacan, and vice versa, even though they were isolated from the brain at the same stage. The reactivity of NGC with lectins and with the HNK-1 antibody markedly changed as the brain matured. These findings indicate that the structure of the carbohydrate moiety of NGC is developmentally regulated, and differs from those of neurocan and phosphacan. The developmentally-regulated structural change of the carbohydrates on NGC may be partly implicated in the modulation of neuronal cell recognition during brain development.
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PMID:Developmental changes in the biochemical and immunological characters of the carbohydrate moiety of neuroglycan C, a brain-specific chondroitin sulfate proteoglycan. 1511 11

The hypothalamic magnocellular neurons, synthesizing arginine vasopressin (AVP) and oxytocin, are well known to show structural plasticity during chronic physiological stimulation. We have previously reported that 6B4 phosphacan/receptor-type protein-tyrosine phosphatasebeta (RPTPbeta), a chondroitin sulfate proteoglycan is highly expressed in the supraoptic nucleus (SON) of adult hypothalamus. Here, we undertook to study the activity-dependent regulation of 6B4 phosphacan/RPTPbeta in this system. Double labeling confocal microscopy demonstrated in the SON that 6B4 phosphacan/RPTPbeta-immunoreactive perineuronal nets were seen around AVP-containing somata and dendrites and its distribution pattern was well coincided with that of TAG-1. Quantitative immunohistochemical and Western analyses showed that 1-week salt loading, known as the chronic physiological stimulation for inducing the structural changes such as synaptic remodeling and direct neuronal membrane apposition, decreased 6B4 phosphacan/RPTPbeta levels in the SON, but did not alter TAG-1 levels. The 6B4 phosphacan/RPTPbeta levels were returned to control basal values within 3 weeks after the cessation of the chronic stimulation. Activity-dependent decreases in 6B4 phosphacan/RPTPbeta levels of the SON were confirmed when Western and immunohistochemical samples were digested with chondroitinase ABC, indicating that the decrease in 6B4 phosphacan/RPTPbeta levels was due to disappearance of 6B4 phosphacan/RPTPbeta core protein rather than increase in chondroitin sulfate glycosaminoglycans. With electron microscopy, the electron-dense immunoproducts for 6B4 phosphacan/RPTPbeta were found on the membrane surface of axons and glial processes, but not at synaptic junctions in control SON, and its immunoreactivity was eliminated with the chronic salt loading. The present results indicate that the levels of 6B4 phosphacan/RPTPbeta are regulated with activity-dependent manner and may be concerned with the structural plasticity seen in the SON.
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PMID:Activity-dependent regulation of a chondroitin sulfate proteoglycan 6B4 phosphacan/RPTPbeta in the hypothalamic supraoptic nucleus. 1526 Nov 12

Helicobacter pylori produces a potent exotoxin, VacA, which causes progressive vacuolation as well as gastric injury. Although VacA was able to interact with two receptor-like protein tyrosine phosphatases, RPTPbeta and RPTPalpha, RPTPbeta was found to be responsible for gastric damage caused by VacA. To define the region of RPTPbeta involved in VacA binding, we made mutants of human cDNA RPTPbeta-B, a short receptor form of RPTPbeta. Immunoprecipitation experiments to assess VacA binding to RPTPbeta-B mutants indicated that five residues (QTTQP) at positions 747-751 of the extracellular domain of RPTPbeta-B (which is commonly retained in RPTPbeta-A, a long form of RPTPbeta) play a crucial role in its interaction with VacA, resulting in vacuolation as well as Git-1 phosphorylation. Transfected cells expressing deletion mutant Delta752, which lacks QTTQP, or the double point mutant Delta747 (T748A,T749A) had diminished vacuolation in response to VacA. Treatment of RPTPbeta-B and Delta747 (which have QTTQP at 747-751) with neuraminidase and O-glycosidase diminished their VacA binding, whereas chondroitinase ABC did not have an effect. No inhibitory effect of pleiotrophin, a natural RPTPbeta ligand, on VacA binding to RPTPbeta-B or Delta747 was observed, supporting the conclusion that the extracellular region of RPTPbeta-B responsible for VacA binding is different from that involved in binding pleiotrophin. These data define the region in the RPTPbeta extracellular domain critical for VacA binding, in particular the sequence QTTQP at positions 747-751 with crucial threonines at positions 748 and 749 and are consistent with a role for terminal sialic acids possibly because of threonine glycosylation.
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PMID:Essential domain of receptor tyrosine phosphatase beta (RPTPbeta) for interaction with Helicobacter pylori vacuolating cytotoxin. 1538 29

After injury to the adult central nervous system (CNS), numerous cytokines and growth factors are released that contribute to reactive gliosis and extracellular matrix production. In vitro examination of these cytokines revealed that the presence of transforming growth factor-beta1 (TGF-beta1) and epidermal growth factor (EGF) greatly increased the production of several chondroitin sulfate proteoglycans (CSPG) by astrocytes. Treatment of astrocytes with other EGF-receptor (ErbB1) ligands, such as TGF-alpha and HB-EGF, produced increases in CSPG production similar to those observed with EGF. Treatment of astrocytes, however, with heregulin, which signals through other members of the EGF-receptor family (ErbB2, ErbB3, ErbB4), did not induce CSPG upregulation. The specificity of activation through the ErbB1 receptor was further verified by using a selective antagonist (AG1478) to this tyrosine kinase receptor. Western blot analysis of astrocyte supernatant pre-digested with chondroitinase ABC indicated the presence of multiple core proteins containing 4-sulfated or 6-sulfated chondroitin. To identify some of these CSPGs, Western blots were screened using antibodies to several known CSPG core proteins. These analyses showed that treatment of astrocytes with EGF increased phosphacan expression, whereas treatment with TGF-beta1 increased neurocan expression. Reverse transcription-polymerase chain reaction (RT-PCR) was used to examine the expression of these molecules in vivo, which result in increased expression of TGF-beta1, EGF-receptor, neurocan, and phosphacan after injury to the brain. These data begin to elucidate some of the injury-induced growth factors that regulate the expression of CSPGs which could be targeted in the future to modulate CSPG production after injury to the central nervous system.
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PMID:Growth factor and cytokine regulation of chondroitin sulfate proteoglycans by astrocytes. 1596 32

We developed a method to extract differentially chondroitin sulfate proteoglycans (CSPGs) that are diffusely present in the central nervous system (CNS) matrix and CSPGs that are present in the condensed matrix of perineuronal nets (PNNs). Adult rat brain was sequentially extracted with Tris-buffered saline (TBS), TBS-containing detergent, 1 m NaCl, and 6 m urea. Extracting tissue sections with these buffers showed that the diffuse and membrane-bound CSPGs were extracted in the first three buffers, but PNN-associated CSPGs remained and were only removed by 6 m urea. Most of the CSPGs were extracted to some degree with all the buffers, with neurocan, brevican, aggrecan, and versican particularly associated with the stable urea-extractable PNNs. The CSPGs in stable complexes only extractable in urea buffer are found from postnatal day 7-14 coinciding with PNN formation. Disaccharide composition analysis indicated a different glycosaminoglycan (GAG) composition for PGs strongly associated with extracellular matrix (ECM). For CS/dermatan sulfate (DS)-GAG the content of nonsulfated, 6-O-sulfated, 2,6-O-disulfated, and 4,6-O-disulfated disaccharides were higher and for heparan sulfate (HS)-GAG, the content of 6-O-sulfated, 2-N-, 6-O-disulfated, 2-O-, 2-N-disulfated, and 2-O-, 2-N-, 6-O-trisulfated disaccharides were higher in urea extract compared with other buffer extracts. Digestions with chondroitinase ABC and hyaluronidase indicated that aggrecan, versican, neurocan, brevican, and phosphacan are retained in PNNs through binding to hyaluronan (HA). A comparison of the brain and spinal cord ECM with respect to CSPGs indicated that the PNNs in both parts of the CNS have the same composition.
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PMID:Composition of perineuronal net extracellular matrix in rat brain: a different disaccharide composition for the net-associated proteoglycans. 1664 27

Chondroitinase treatment of experimental spinal cord injury improves recovery of sensory, motor, and autonomic functions. Chondroitinase catalyzes the cleavage of glycosaminoglycans (GAGs) from the core proteins of chondroitin sulfate proteoglycans (CSPGs). Little is known about changes in production of these proteoglycans in the clinically relevant contusion model of spinal cord injury or if CSPG content is altered by chondroitinase treatment. Female Long-Evans rats were injured with a forceps contusion injury and treated on alternate days with chondroitinase ABCI or control enzyme via an intrathecal catheter. Spinal cords were analyzed at specific times after injury. The cord was divided in 4 mm long segments, one containing the lesion, two rostral and two caudal to the lesion. These segments were assessed for CSPG protein and message content (NG2, neurocan and phosphacan) by Western blotting and real-time PCR. CSPG protein content was increased by one day post injury for all CSPGs investigated, and was increased in all segments examined rostral and caudal to the lesion site. Significant increases in CSPG were observed with peak content detected at 7, 7 and 14 days post injury for NG2, neurocan and phosphacan, respectively. Chondroitinase treatment had little impact upon the CPSG protein content. Changes in message levels of these CSPGs are also reported. This demonstrates that expression patterns of CSPGs in contusion injury are similar to those surrounding surgical hemisection lesions and demonstrates that the sensory and motor function enhancing effects of chondroitinase are likely due to removal of GAG chains rather than reduction in CSPG content.
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PMID:Chondroitin sulfate proteoglycans in spinal cord contusion injury and the effects of chondroitinase treatment. 1800 Dec 3

Perineuronal nets (PNNs) are dense extracellular matrix (ECM) structures that form around many neuronal cell bodies and dendrites late in development. They contain several chondroitin sulphate proteoglycans (CSPGs), hyaluronan, link proteins and tenascin-R. Their time of appearance correlates with the ending of the critical period for plasticity, and they have been implicated in this process. The distribution of PNNs in the spinal cord was examined using Wisteria floribunda agglutinin lectin and staining for chondroitin sulphate stubs after chondroitinase digestion. Double labelling with the neuronal marker, NeuN, showed that PNNs were present surrounding approximately 30% of motoneurons in the ventral horn, 50% of large interneurons in the intermediate grey and 20% of neurons in the dorsal horn. These PNNs formed in the second week of postnatal development. Immunohistochemical staining demonstrated that the PNNs contain a mixture of CSPGs, hyaluronan, link proteins and tenascin-R. Of the CSPGs, aggrecan was present in all PNNs while neurocan, versican and phosphacan/RPTPbeta were present in some but not all PNNs. In situ hybridization showed that aggrecan and cartilage link protein (CRTL 1) and brain link protein-2 (BRAL 2) are produced by neurons. PNN-bearing neurons express hyaluronan synthase, and this enzyme and phosphacan/RPTPbeta may attach PNNs to the cell surface. During postnatal development the expression of link protein and aggrecan mRNA is up-regulated at the time of PNN formation, and these molecules may therefore trigger their formation.
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PMID:Distribution and synthesis of extracellular matrix proteoglycans, hyaluronan, link proteins and tenascin-R in the rat spinal cord. 1836 19

Chondroitin sulfate proteoglycans (CSPGs) consist of chondroitin sulfate (CS) glycosaminoglycans (GAGs) and core protein and regulate the migration, axonal outgrowth, and synaptogenesis in mammalian brains. In the present study, we investigated the localization of CSPGs, the effects of sensory deprivation on the density of perineuronal nets (PNNs), and the effects of chondroitinase ABC (Chase) on the formation of barrel structures in the posterior medial barrel subfield (PMBSF). In developing mouse and rat brains, the immunoreactivity of chondroitin-6-sulfate containing proteoglycan (CS-6-PG), phosphacan, and neurocan was stronger at barrel septa as compared with barrel hollows and surrounding cortex, while the labeling of Wisteria floribunda agglutinin (WFA) was observed at barrel hollows. In adult brains, CS-6-PG-immunoreactive and WFA-labeled PNNs were observed mainly at barrel hollows of mouse, but they were seen chiefly at barrel septa of rats. Sensory deprivation of facial vibrissae reduced the number of WFA-labeled PNNs at barrel hollows but not at barrel septa. Intracerebral injection of Chase did not affect the formation of barrel structures in the PMBSF. These data indicate species-dependent heterogeneity of CSPG expression and activity-dependent formation of PNNs in the PMBSF, but CS GAGs have no crucial function in constructing the barrel structures during early postnatal development.
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PMID:Expression of chondroitin sulfate proteoglycans in barrel field of mouse and rat somatosensory cortex. 1905 58


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