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Calpain‐cleaved type 1 inositol 1,4,5‐trisphosphate receptor impairs ER Ca 2+ buffering and causes neurodegeneration in primary cortical neurons
Author(s) -
Kopil Catherine M.,
Siebert Adam P.,
Kevin Foskett J.,
Neumar Robert W.
Publication year - 2012
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2012.07859.x
Subject(s) - neurodegeneration , calpain , proteolysis , inositol trisphosphate receptor , microbiology and biotechnology , endoplasmic reticulum , inositol , glutamate receptor , biology , receptor , programmed cell death , homeostasis , inositol trisphosphate , chemistry , biochemistry , apoptosis , medicine , disease , enzyme
Abstract Disruption of neuronal Ca 2+ 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 (InsP 3 R1), a Ca 2+ release channel on the endoplasmic reticulum, generates a dysregulated channel, which may contribute to aberrant Ca 2+ signaling and neurodegeneration in disease states. However, the specific effects of InsP 3 R1 proteolysis on neuronal Ca 2+ homeostasis are unknown, as are the functional contributions of this pathway to neuronal death. This study evaluates the consequences of calpain‐mediated InsP 3 R1 proteolysis on neuronal Ca 2+ signaling and survival using adeno‐associated viruses to express a recombinant cleaved form of the channel (capn‐InsP 3 R1) in rat primary cortical neurons. Here, we demonstrate that expression of capn‐InsP 3 R1 in cortical cultures reduced cellular viability. This effect was associated with increased resting cytoplasmic Ca 2+ concentration ([Ca 2+ ] i ), increased [Ca 2+ ] i response to glutamate, and enhanced sensitivity to excitotoxic stimuli. Together, our results demonstrate that InsP 3 R1 proteolysis disrupts neuronal Ca 2+ homeostasis, and potentially acts as a feed‐forward pathway to initiate or execute neuronal death.