Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q8IXL6 (RNS)
 1,091 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overactivation of the NMDA-subtype of glutamate receptor is known to trigger excessive calcium influx, contributing to neurodegenerative conditions. Such dysregulation of calcium signaling results in generation of excessive free radicals, including reactive oxygen and nitrogen species (ROS/RNS), including nitric oxide (NO). In turn, we and our colleagues have shown that these free radicals trigger pathological production of misfolded proteins, mitochondrial dysfunction, and apoptotic pathways in neuronal cells. Here, we discuss emerging evidence that excessive calcium-induced NO production can contribute to the accumulation of misfolded proteins, specifically by S-nitrosylation of the ubiquitin E3 ligase, parkin, and the chaperone enzyme for nascent protein folding, protein-disulfide isomerase. Additionally, excessive calcium-induced NO generation leads to the formation of S-nitrosylated dynamin-related protein 1, which causes abnormal mitochondrial fragmentation and resultant synaptic damage. In this review, we also discuss how two novel classes of pharmacological agents hold promise to interrupt these pathological processes. Firstly, the NMDA receptor antagonists, Memantine and NitroMemantine, block excessive extrasynaptic glutamate excitation while maintaining synaptic transmission, thereby limiting excessive calcium influx and production of ROS/RNS. Secondly, therapeutic pro-electrophiles are activated in the face of oxidative insult, thus protecting cells from calcium-induced oxidative stress via the Keap1/Nrf2 transcriptional pathway.
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PMID:Preventing Ca2+-mediated nitrosative stress in neurodegenerative diseases: possible pharmacological strategies. 2006 Jan 65

Oxidative and nitrosative stress result in the accumulation of reactive oxygen and nitrogen species (ROS/RNS) which trigger redox-mediated signaling cascades through posttranslational modifications on cysteine residues, including S-nitrosylation (P-SNO) and S-glutathionylation (P-SSG). Protein disulfide isomerase (PDI) is the most abundant chaperone in the endoplasmic reticulum and facilitates protein folding via oxidoreductase activity. Prolonged or acute nitrosative stress blunts the activity of PDI through the formation of PDI-SNO and PDI-SSG. The functional implication is that reduced activity for the period of time leads to an accumulation of misfolded or unfolded proteins and activation of the unfolded protein response. Redox regulation of PDI and downstream signaling events provides an integration point for the functional determination of cell survival pathways. Herein, we describe the methodologies to globally identify S-glutathionylated targets of ROS/RNS; validate and identify the specific cysteine targets and characterize the structural and functional consequences.
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PMID:Nitrosative stress-induced S-glutathionylation of protein disulfide isomerase. 2126 58