title: Calpain-cleaved type 1 inositol 1,4,5-trisphosphate receptor impairs ER Ca(2+)  buffering and causes neurodegeneration in primary cortical neurons.
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.
authors: Department of Emergency Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors: Catherine M
authors: CM
authors: Kopil
authors: Adam P
authors: AP
authors: Siebert
authors: J Kevin
authors: JK
authors: Foskett
authors: Robert W
authors: RW
authors: Neumar
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002461:Cell Line, Transformed; D002470:Cell Survival; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D018698:Glutamic Acid / Q000633:toxicity; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism*; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D009410:Nerve Degeneration / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D017354:Point Mutation / Q000235:genetics; D011247:Pregnancy; D051381:Rats; D019284:Thapsigargin / Q000494:pharmacology; D014162:Transfection
chemical_list: D004791:Enzyme Inhibitors; D053496:Inositol 1,4,5-Trisphosphate Receptors; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D018698:Glutamic Acid; D008734:Methoxyhydroxyphenylglycol; D019284:Thapsigargin; D002118:Calcium; C010117:3,4-dihydroxyphenylglycol