Calpain-cleaved type 1 inositol 1,4,5-trisphosphate receptor impairs ER Ca2+ buffering and causes neurodegeneration in primary cortical neurons
Article first published online: 14 AUG 2012
© 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry
Journal of Neurochemistry
Volume 123, Issue 1, pages 147–158, October 2012
How to Cite
Kopil, C. M., Siebert, A. P., Kevin Foskett, J. and Neumar, R. W. (2012), Calpain-cleaved type 1 inositol 1,4,5-trisphosphate receptor impairs ER Ca2+ buffering and causes neurodegeneration in primary cortical neurons. Journal of Neurochemistry, 123: 147–158. doi: 10.1111/j.1471-4159.2012.07859.x
- Issue published online: 10 SEP 2012
- Article first published online: 14 AUG 2012
- Accepted manuscript online: 4 JUL 2012 02:40PM EST
- Received April 27, 2012; revised manuscript received June 21, 2012; accepted June 26, 2012.
- endoplasmic reticulum;
- inositol 1,4,5-trisphosphate receptor;
Disruption of neuronal Ca2+ homeostasis plays a well-established role in cell death in a number of neurodegenerative disorders. Recent evidence suggests that proteolysis of the type 1 inositol 1,4,5-trisphosphate receptor (InsP3R1), a Ca2+ release channel on the endoplasmic reticulum, generates a dysregulated channel, which may contribute to aberrant Ca2+ signaling and neurodegeneration in disease states. However, the specific effects of InsP3R1 proteolysis on neuronal Ca2+ homeostasis are unknown, as are the functional contributions of this pathway to neuronal death. This study evaluates the consequences of calpain-mediated InsP3R1 proteolysis on neuronal Ca2+ signaling and survival using adeno-associated viruses to express a recombinant cleaved form of the channel (capn-InsP3R1) in rat primary cortical neurons. Here, we demonstrate that expression of capn-InsP3R1 in cortical cultures reduced cellular viability. This effect was associated with increased resting cytoplasmic Ca2+ concentration ([Ca2+]i), increased [Ca2+]i response to glutamate, and enhanced sensitivity to excitotoxic stimuli. Together, our results demonstrate that InsP3R1 proteolysis disrupts neuronal Ca2+ homeostasis, and potentially acts as a feed-forward pathway to initiate or execute neuronal death.