Dysregulation of Ca 2+ signaling following oxidative stress is an important pathophysiological mechanism of many chronic neurodegenerative disorders, including Alzheimer's Disease, agerelated macular degeneration, glaucomatous and diabetic retinopathies. However, the underlying mechanisms of disturbed intracellular Ca 2+ signaling remain largely unknown. We here describe a novel mechanism for increased intracellular Ca 2+ release following oxidative stress in a neuronal cell line. Using an experimental approach that included quantitative polymerase chain reaction, quantitative immunoblotting, microfluorimetry and the optical imaging of intracellular Ca 2+ release, we show that sub-lethal tert-butyl hydroperoxide-mediated oxidative stress result in a selective up-regulation of type-2 inositol-1,4,5,-trisphophate receptors. This oxidative stress mediated change was detected both at the transcriptional and translational level and functionally resulted in increased Ca 2+ release into the nucleoplasm from the membranes of the nuclear envelope at a given receptor-specific stimulus. Our data describe a novel source of Ca 2+ dysregulation induced by oxidative stress with potential relevance for differential subcellular Ca 2+ signaling specifically within the nucleus and the development of novel neuroprotective strategies in neurodegenerative disorders.
Inositol 1, 4, 5-trisphosphate (IP3) receptor associated cyclic GMP (cGMP) kinase substrate (IRAG, also known as Mrv1) is a type-2 integral membrane endoplasmic reticulum (ER) protein, which interacts with IP3 Receptor type 1 (IP3R1), cGMP kinase I-β (cGKI β) and other associated proteins. It plays a key role in NO, cGMP, and cGKI β mediated inhibition of IP3R1 activity and thus relaxes smooth muscle tone and inhibits platelet aggregation. As a scaffolding protein Mrv1 maintains the conformation of a heteroprotein complex containing cGKI β, IP3R1 and other proteins and enables efficient activity of cGKI β within the complex. Increased expression of Mrv1 or IRAG in the absence of tumor related transcription factor in pancreatic cancer cells suggest that it might be involved in tumorigenesis. Downregulation of Mrv1 during megakaryocyte maturation indicates that it is involved in cell growth and differentiation.
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