Abstract
Membrane localization of voltage gated sodium channels following calpain mediated proteolysis
Journal of neurotrauma, v 25(7), pp 877-877
Jul 2008
Abstract
Targets of calpain activation following traumatic brain injury (TBI) and ischemia include ligand and voltage gated ion channels. We propose that the voltage gated sodium channel (NaCh) is an additional calpain substrate. Proteolysis of this channel occurs in models of both in-vivo and in-vitro traumatic brain injury. We previously demonstrated a calpain dependency for proteolysis during elevated Ca2 in rat brain homogenates, pharmacological disruption of ionic homeostasis, and stretch injury. In this study, we investigated the protease specificity for the NaChas well as the localization of proteolyzed channels to gain insight on the functional significance of proteolysis. Calpain is known to interact with other proteotolytic pathways, affecting both caspase and cathepsin activity. Therefore, NaCh proteolysis could be a downstream rather than direct effect of calpain activation. A model of disrupted ionic homeostasis through the Ca2ionophore ionomycin was used to induce proteolysis of the NaCh. Proteolysis was prevented upon pre-treatment with the calpain inhibitor MDL28170 and required the presence of calcium. Inhibition of the caspases (Z-VAD-FMK), the cathepsins (Mu-Phe-hPhe-FMK) and the proteosome (lactacystin) did not significantly decrease proteolysis. Interestingly, preventing clather in mediated endocytosis by inhibit-ing dynamin (Dynasore) did not decrease the amount of proteolysis, implying that internalization is not necessary for proteolysis. In support of this, surface biotinylation following ionophore treatment identified both the full length and truncated form of the channel, indicating that modified channels remain at the sur-face. This data suggests that calpain specifically targets and modifies NaChs expressed at the surface upon increases in intracellular calcium, potentially altering action potential initiation and propagation after injury.
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Details
- Title
- Membrane localization of voltage gated sodium channels following calpain mediated proteolysis
- Creators
- Catherine R von Reyn - University of PennsylvaniaDavid F. Meaney - University of Pennsylvania
- Publication Details
- Journal of neurotrauma, v 25(7), pp 877-877
- Conference
- 26th Annual National Neurotrauma Society Symposium, 26th (Orlando, Florida, United States, 27 Jul 2008–30 Jul 2008)
- Publisher
- Mary Ann Liebert
- Number of pages
- 1
- Resource Type
- Abstract
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Other Identifier
- 991019520115204721