Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344329 (collapse)
 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

When associated with the Nogo receptor (NgR), the transmembrane receptor p75NTR signals growth cone collapse. Arrest of CNS axon growth in vivo is mediated by CNS myelin-derived inhibitory ligands through either an unknown pathway after NgR- and Ca2+-dependent activation of the epidermal growth factor receptor (EGFR), and/or sequential Rho-A/ROCK/LIM-kinase/cofilin phosphorylation leading to actin depolymerization. Paradoxically, rat retinal ganglion cell (RGC) axons regenerate through the CNS myelin-rich transected optic nerve after intravitreal sciatic nerve grafting without inhibitory ligand neutralization. Here, we show that optic nerve regeneration in vivo correlates with Schwann cell-derived factor-induced cleavage of NgR and Nogo-A, and inactivation of p75NTR signalling by the induction of regulated intramembranous proteolysis (RIP) and the release of both extracellular (p75ECD) and intracellular (p75ICD) domains. Hence, Schwann cell-derived factors compromise inhibitory signalling by (i) antagonizing ligand/NgR binding with metalloproteinase-cleaved Nogo-A peptides; (ii) RIP of p75NTR; (iii) competitively blocking NgR/p75NTR clustering with soluble p75ECD; and (iv) consequent reduced downstream EGFR phosphorylation and suppression of Rho-A activation. Moreover, in RGC cultures, exogenous tumour necrosis- converting enzyme (TACE) initiates RIP of p75NTR, reduces EGFR phosphorylation, suppresses activation of Rho-A, cleaves the ECD from both NgR and TROY, and disinhibits neurotrophic factor (NTF) stimulated RGC neurite outgrowth in the presence of CNS myelin. Soluble NgRECD binds all CNS myelin-derived ligands and thus has the potential to act as an inhibitory signalling antagonist, but the role of TROY and its shed ectodomain in growth cone mobility is unknown. siRNA knockdown of p75NTR also inactivates Rho-A and disinhibits NTF-stimulated RGC neurite outgrowth in cultures with added CNS myelin. In all the above experimental paradigms, Schwann cell-derived factor/NTF-induced attenuation of NgR/p75NTR signalling suppresses EGFR activation, thereby potentiating axon growth disinhibition.
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PMID:Schwann cell-derived factor-induced modulation of the NgR/p75NTR/EGFR axis disinhibits axon growth through CNS myelin in vivo and in vitro. 1661 94

After binding, central nervous system (CNS) myelin-derived axon growth inhibitory ligands, the Nogo-66 receptor (NgR), complexes with LINGO-1 and either the low-affinity neurotrophin receptor (p75(NTR)) or TROY to initiate growth cone collapse via a Rho-A inhibitory signaling pathway and/or Ca(2+)-dependent activation of epidermal growth factor receptor (EGFR) through an unknown signaling pathway. We have shown that axon growth through CNS myelin is disinhibited after neurotrophic factor administration by 1) initiating intramembranous proteolysis (RIP) of p75(NTR), leading to cleavage of the extracellular (p75(ECD)) and intracellular domains (p75(ICD)) by alpha- and gamma-secretase, respectively, thereby paralyzing inhibitory signaling; 2) shedding of soluble NgR(ECD), which acts as a competitive antagonist to NgR for binding of inhibitory ligands; and 3) antagonizing NgR/p75(NTR) clustering by competitive p75(ECD)/NgR interaction. Here, we report that TNF-alpha converting enzyme (TACE) (a disintegrin and metalloproteinase 17, ADAM17) induces disinhibition of FGF2-stimulated neurite outgrowth of dorsal root ganglion neurons (DRGN) cultured in the presence of a predetermined concentration of inhibitory CNS myelin-derived ligands. After addition of TACE (which has alpha-secretase activity) to mitotically arrested adult rat mixed DRG cultures, we demonstrate 1) NgR(ECD) shedding; 2) release of p75(ECD) and p75(ICD) by RIP of p75(NTR); 3) blockade of Rho-A activation; 4) reduced EGFR phosphorylation; and 5) increased FGF2-stimulated DRGN neurite outgrowth and branching in the presence of CNS myelin-derived inhibitory ligands. Thus, TACE-induced cleavage of NgR and RIP of p75(NTR) abrogates axon growth inhibitory signaling, thereby disinhibiting CNS axon/neurite growth.
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PMID:TACE-induced cleavage of NgR and p75NTR in dorsal root ganglion cultures disinhibits outgrowth and promotes branching of neurites in the presence of inhibitory CNS myelin. 1684 93

We recently found that the antioxidant ability was remarkably decreased in the hippocampus (Hipp) of EL at 8 weeks of age utilizing ESR spectroscopy. In this study, in addition to evaluating the extracellular glutamate concentration, we tried to determine whether or not changes in the expression of cystine/glutamate exchanger (xCT) and glutamate transporter take place in the Hipp of EL. EL mice and DDY mice at 5, 10, and 20 weeks of age were used for Exp. I and II, respectively. Exp. I: During the interictal state, dialysate was collected from the ventral Hipp using a microdialysis technique, and an extracellular concentration of glutamate ([Glu](o)) was measured with HPLC-ECD. Exp. II: The hippocampal expression of the glutamate transporter and xCT was estimated by Western blots. Exp. I: The level of [Glu](o) at 10 weeks of age was remarkably higher at other ages of EL mice, while [Glu](o) of DDY was unchanged as a result of age. Exp. II: The excitatory amino acid carrier-1 (EAAC-1) and xCT of EL mice at 10 weeks of age decreased more than those of DDY. GLAST and GLT-1 of EL mice at 5 weeks of age decreased more than those of DDY at the same age. No differences were found between EL and DDY for GLAST and GLT-1 at other ages. According to previous studies, the decreased endogenous antioxidant potential observed at 10 weeks of age is a very likely explanation for ictogenesis. The decreased xCT expression at 10 weeks of age could provide the molecular mechanism to explain the depletion of the endogenous antioxidant ability of EL mice during ictogenesis. In addition to the depletion of antioxidant ability, decreased EAAC-1 at this period could be one reason for the collapse of the molecular action of inhibition. These molecular findings support the idea that the elevation of [Glu](o) at 10 weeks of age triggers ictogenesis.
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PMID:Molecular regulation of antioxidant ability in the hippocampus of EL mice. 1862 Oct 28

Conformational properties of a 12-residue tryptophan zipper (trpzip) beta-hairpin peptide (AWAWENGKWAWK-NH(2), a modification of the original trpzip2 sequence) are analyzed under equilibrium conditions using ECD and IR spectra of a series of variants, singly and doubly C(1)-labeled with (13)C on the amide CO. The characteristic features of the (13)CO component of the amide I' IR band and their sensitivity to the local structure of the peptide are used to differentiate stabilities for parts of the hairpin structure. Doubly labeled peptide spectra indicate that the ends of the beta-strands are frayed and that the center part is more stable as would be expected from formation of a stable hydrophobic core consisting of four tryptophan residues, and supported by MD simulations. NMR analyses were used to determine a best fit solution structure that is in close agreement with that of trpzip2, except for a small variation in the turn geometry. The distinct vibrational coupling patterns of the labeled sites based on this structure are also well matched by ab initio DFT-level calculations of their IR spectral patterns. Thermal unfolding of the peptides as studied with CD spectra could be fit with an apparent two-state transition model. ECD senses only the tryptophan interactions (tertiary-like) and their overall environment, as shown by TD-DFT modeling of the Trp-Trp pi-pi ECD. However, variation of the amide I IR spectra of (13)C-isotopomers showed that the thermal unfolding process is not cooperative in terms of the peptide backbone (secondary structure), since the transition temperatures sensed for labeled modes differ from those for the whole peptide. The thermal data also evidence dependence on concentration and pH but these cause little spectral variation. This study illustrates the consequences of multistate conformational change at the residue- or sequence-specific level in a system whose structure is dominated by hydrophobic collapse.
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PMID:Cross-strand coupling and site-specific unfolding thermodynamics of a trpzip beta-hairpin peptide using 13C isotopic labeling and IR spectroscopy. 1932 92