Journal article
Mechanisms of calpain mediated proteolysis of voltage gated sodium channel alpha-subunits following in vitro dynamic stretch injury
Journal of neurochemistry, v 121(5), pp 793-805
01 Jun 2012
PMID: 22428606
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Although enhanced calpain activity is well documented after traumatic brain injury (TBI), the pathways targeting specific substrate proteolysis are less defined. Our past work demonstrated that calpain cleaves voltage gated sodium channel (NaCh) a-subunits in an in vitro TBI model. In this study, we investigated the pathways leading to NaCh cleavage utilizing our previously characterized in vitro TBI model, and determined the location of calpain activation within neuronal regions following stretch injury to micropatterned cultures. Calpain specific breakdown products of a-spectrin appeared within axonal, dendritic, and somatic regions 6 h after injury, concurrent with the appearance of NaCh a-subunit proteolysis in both whole cell or enriched axonal preparations. Direct pharmacological activation of either NMDA receptors (NMDArs) or NaChs resulted in NaCh proteolysis. Likewise, a chronic (6 h) dual inhibition of NMDArs/NaChs but not L-type voltage gated calcium channels significantly reduced NaCh proteolysis 6 h after mechanical injury. Interestingly, an early, transient (30 min) inhibition of NMDArs alone significantly reduced NaCh proteolysis. Although a chronic inhibition of calpain significantly reduced proteolysis, a transient inhibition of calpain immediately after injury failed to significantly attenuate NaCh proteolysis. These data suggest that both NMDArs and NaChs are key contributors to calpain activation after mechanical injury, and that a larger temporal window of sustained calpain activation needs consideration in developing effective treatments for TBI.
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Details
- Title
- Mechanisms of calpain mediated proteolysis of voltage gated sodium channel alpha-subunits following in vitro dynamic stretch injury
- Creators
- Catherine R. von Reyn - University of PennsylvaniaRosalind E. Mott - University of PennsylvaniaRobert Siman - University of PennsylvaniaDouglas H. Smith - University of PennsylvaniaDavid F. Meaney (Corresponding Author) - University of Pennsylvania
- Publication Details
- Journal of neurochemistry, v 121(5), pp 793-805
- Publisher
- Wiley
- Number of pages
- 13
- Grant note
- R01HD041699 / EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) P01-NS-015202; NS 35712; HD41699 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA P01NS056202 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:000303387800012
- Scopus ID
- 2-s2.0-84860541732
- Other Identifier
- 991019176639604721
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InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Web of Science research areas
- Biochemistry & Molecular Biology
- Neurosciences