CXCL10-induced cell death in neurons: Role of calcium dysregulation
Sui, Yongjun Stehno-Bittel, Lisa Li, Shanping Loganathan, Rajprasad Dhillon, Navneet K. Pinson, David Nath, Avindra Kolson, Dennis Narayan, Opendra Buch, Shilpa
Sui, Yongjun
Stehno-Bittel, Lisa
Li, Shanping
Loganathan, Rajprasad
Dhillon, Navneet K.
Pinson, David
Nath, Avindra
Kolson, Dennis
Narayan, Opendra
Buch, Shilpa
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2006-03-02
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Article
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Keywords
Caspases,Chemokine,CXCL10,HIV-associated dementia,Human neuronal apoptosis
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Citation
Sui, Y., Stehno-Bittel, L., Li, S., Loganathan, R., Dhillon, N.K., Pinson, D., Nath, A., Kolson, D., Narayan, O. and Buch, S. (2006), CXCL10-induced cell death in neurons: role of calcium dysregulation. European Journal of Neuroscience, 23: 957-964. https://doi.org/10.1111/j.1460-9568.2006.04631.x
Abstract
Chemokines play a key role in the regulation of central nervous system disease. CXCL10 over-expression has been observed in several neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease and HIV-associated dementia. More recent studies by others and us have shown that CXCL10 elicits apoptosis in fetal neurons. The mechanism of CXCL10-mediated neurotoxicity, however, remains unclear. In this study, we provide evidence for the direct role of Ca2+ dysregulation in CXCL10-mediated apoptosis. We demonstrate that treatment of fetal neuronal cultures with exogenous CXCL10 produced elevations in intracellular Ca2+ and that this effect was modulated via the binding of CXCL10 to its cognate receptor, CXCR3. We further explored the association of intracellular Ca2+ elevations with the caspases that are involved in CXC10-induced neuronal apoptosis. Our data showed that increased Ca2+, which is available for uptake by the mitochondria, is associated with membrane permeabilization and cytochrome c release from this compartment. The released cytochrome c then activates the initiator active caspase-9. This initiator caspase sequentially activates the effector caspase-3, ultimately leading to apoptosis. This study identifies the temporal signaling cascade involved in CXCL10-mediated neuronal apoptosis and provides putative targets for pharmaceutical intervention of neurological disorders associated with CXCL10 up-regulation.
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Description
Article first published online: 2006-03-02. Issue published: 2006-02.
Publisher
John Wiley & Sons Ltd
Federation of European Neuroscience Societies
Federation of European Neuroscience Societies
Journal
European Journal of Neuroscience
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ISSN
1460-9568
0953-816X
0953-816X