Calpain Mediates Proteolysis of the Voltage-Gated Sodium Channel α-Subunit

Reyn, Catherine R. von; Spaethling, Jennifer M.; Mesfin, Mahlet N.; Ma, Marek; Neumar, Robert W.; Smith, Douglas H.; Siman, Robert; Meaney, David F.

doi:10.1523/jneurosci.2339-09.2009

Cited by 84 publications

(97 citation statements)

References 26 publications

(32 reference statements)

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“…33,96 In addition, proteolysis of the sodium channel inactivation gate by calcium activated protease, calpain, was found to lead to persistent increases in intra-axonal calcium. 160 Release of intra-axonal calcium stores after injury has also been observed. 98 These effects represent potential therapeutic targets using agents that block sodium channels, calcium channels, and sodium-calcium exchangers or by calpain inhibition as described below.…”

Section: Ion Homeostasismentioning

confidence: 99%

Therapy Development for Diffuse Axonal Injury

Smith

Hicks

Povlishock

2013

Journal of Neurotrauma

174

146

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Diffuse axonal injury (DAI) remains a prominent feature of human traumatic brain injury (TBI) and a major player in its subsequent morbidity. The importance of this widespread axonal damage has been confirmed by multiple approaches including routine postmortem neuropathology as well as advanced imaging, which is now capable of detecting the signatures of traumatically induced axonal injury across a spectrum of traumatically brain-injured persons. Despite the increased interest in DAI and its overall implications for brain-injured patients, many questions remain about this component of TBI and its potential therapeutic targeting. To address these deficiencies and to identify future directions needed to fill critical gaps in our understanding of this component of TBI, the National Institute of Neurological Disorders and Stroke hosted a workshop in May 2011. This workshop sought to determine what is known regarding the pathogenesis of DAI in animal models of injury as well as in the human clinical setting. The workshop also addressed new tools to aid in the identification of this axonal injury while also identifying more rational therapeutic targets linked to DAI for continued preclinical investigation and, ultimately, clinical translation. This report encapsulates the oral and written components of this workshop addressing key features regarding the pathobiology of DAI, the biomechanics implicated in its initiating pathology, and those experimental animal modeling considerations that bear relevance to the biomechanical features of human TBI. Parallel considerations of alternate forms of DAI detection including, but not limited to, advanced neuroimaging, electrophysiological, biomarker, and neurobehavioral evaluations are included, together with recommendations for how these technologies can be better used and integrated for a more comprehensive appreciation of the pathobiology of DAI and its overall structural and functional implications. Lastly, the document closes with a thorough review of the targets linked to the pathogenesis of DAI, while also presenting a detailed report of those target-based therapies that have been used, to date, with a consideration of their overall implications for future preclinical discovery and subsequent translation to the clinic. Although all participants realize that various research gaps remained in our understanding and treatment of this complex component of TBI, this workshop refines these issues providing, for the first time, a comprehensive appreciation of what has been done and what critical needs remain unfulfilled.

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Section: Ion Homeostasismentioning

confidence: 99%

Therapy Development for Diffuse Axonal Injury

Smith

Hicks

Povlishock

2013

Journal of Neurotrauma

174

146

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“…These include ␣II-spectrin (Siman et al, 1984;Nixon, 1986), actin (Villa et al, 1998), glutamate receptors (Bi et al, 1997;Xu et al, 2007), the postsynaptic density-95 protein (Gascó n et al, 2008), the Na ϩ /Ca 2ϩ exchanger (Bano et al, 2005), ankyrinG (Schafer et al, 2009), the voltage-gated sodium channel ␣ subunit (von Reyn et al, 2009), and the plasma membrane Ca 2ϩ -ATPase (Pottorf et al, 2006). However, whether calpain plays a role in neuronal Cl Ϫ regulation is unknown.…”

Section: Introductionmentioning

confidence: 99%

Activity-Dependent Cleavage of the K-Cl Cotransporter KCC2 Mediated by Calcium-Activated Protease Calpain

et al. 2012

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The K-Cl cotransporter KCC2 plays a crucial role in neuronal chloride regulation. In mature central neurons, KCC2 is responsible for the low intracellular Cl Ϫ concentration ([Cl Ϫ ] i ) that forms the basis for hyperpolarizing GABA A receptor-mediated responses. Fast changes in KCC2 function and expression have been observed under various physiological and pathophysiological conditions. Here, we show that the application of protein synthesis inhibitors cycloheximide and emetine to acute rat hippocampal slices have no effect on total KCC2 protein level and K-Cl cotransporter function. Furthermore, blocking constitutive lysosomal degradation with leupeptin did not induce significant changes in KCC2 protein levels. These findings indicate a low basal turnover rate of the total KCC2 protein pool. In the presence of the glutamate receptor agonist NMDA, the total KCC2 protein level decreased to about 30% within 4 h, and this effect was blocked by calpeptin and MDL-28170, inhibitors of the calcium-activated protease calpain. Interictal-like activity induced by incubation of hippocampal slices in an Mg 2ϩ -free solution led to a fast reduction in KCC2-mediated Cl Ϫ transport efficacy in CA1 pyramidal neurons, which was paralleled by a decrease in both total and plasmalemmal KCC2 protein. These effects were blocked by the calpain inhibitor MDL-28170. Taken together, these findings show that calpain activation leads to cleavage of KCC2, thereby modulating GABAergic signaling.

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“…25 These results were further confirmed by von Reyn and colleagues, that calpain-mediated proteolysis of the sodium channel a subunit within the I -II and III-IV loops of Na v 1.2; however, the authors indicated that sites of proteolysis might differ between a subunit. 26 Their further study reported that calpain activation and subsequent proteolysis of sodium channel a subunit were mediated by NMDA receptors and sodium channels following stretch injury. 27 A recent in vivo study employed a novel calpastain overexpressing transgenic mouse model and demonstrated that augmenting calpastatin levels attenuated calpain-mediated proteolysis of sodium channels.…”

Section: Discussionmentioning

confidence: 99%

Blockage of the Upregulation of Voltage-Gated Sodium Channel Na_v1.3 Improves Outcomes after Experimental Traumatic Brain Injury

Huang

Lin

et al. 2014

Journal of Neurotrauma

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Excessive active voltage-gated sodium channels are responsible for the cellular abnormalities associated with secondary brain injury following traumatic brain injury (TBI). We previously presented evidence that significant upregulation of Na v 1.3 expression occurs in the rat cortex at 2 h and 12 h post-TBI and is correlated with TBI severity. In our current study, we tested the hypothesis that blocking upregulation of Na v 1.3 expression in vivo in the acute stage post-TBI attenuates the secondary brain injury associated with TBI. We administered either antisense oligodeoxynucleotides (ODN) targeting Na v 1.3 or artificial cerebrospinal fluid (aCSF) at 2 h, 4 h, 6 h, and 8 h following TBI. Control sham animals received aCSF administration at the same time points. At 12 h post-TBI, Na v 1.3 messenger ribonucleic acid (mRNA) levels in bilateral hippocampi of the aCSF group were significantly elevated, compared with the sham and ODN groups ( p < 0.01). However, the Na v 1.3 mRNA levels in the uninjured contralateral hippocampus of the ODN group were significantly lowered, compared with the sham group ( p < 0.01). Treatment with antisense ODN significantly decreased the number of degenerating neurons in the ipsilateral hippocampal CA3 and hilar region ( p < 0.01). A set of left-to-right ratio value analyzed by magnetic resonance imaging T2 image on one day, three days, and seven days post-TBI showed marked edema in the ipsilateral hemisphere of the aCSF group, compared with that of the ODN group ( p < 0.05). The Morris water maze memory retention test showed that both the aCSF and ODN groups took longer to find a hidden platform, compared with the sham group ( p < 0.01). However, latency in the aCSF group was significantly higher than in the ODN group ( p < 0.05). Our in vivo Na v 1.3 inhibition studies suggest that therapeutic strategies to block upregulation of Na v 1.3 expression in the brain may improve outcomes following TBI.

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Calpain Mediates Proteolysis of the Voltage-Gated Sodium Channel α-Subunit

Cited by 84 publications

References 26 publications

Therapy Development for Diffuse Axonal Injury

Therapy Development for Diffuse Axonal Injury

Activity-Dependent Cleavage of the K-Cl Cotransporter KCC2 Mediated by Calcium-Activated Protease Calpain

Blockage of the Upregulation of Voltage-Gated Sodium Channel Na_v1.3 Improves Outcomes after Experimental Traumatic Brain Injury

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Calpain Mediates Proteolysis of the Voltage-Gated Sodium Channel α-Subunit

Cited by 84 publications

References 26 publications

Therapy Development for Diffuse Axonal Injury

Therapy Development for Diffuse Axonal Injury

Activity-Dependent Cleavage of the K-Cl Cotransporter KCC2 Mediated by Calcium-Activated Protease Calpain

Blockage of the Upregulation of Voltage-Gated Sodium Channel Nav1.3 Improves Outcomes after Experimental Traumatic Brain Injury

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Blockage of the Upregulation of Voltage-Gated Sodium Channel Na_v1.3 Improves Outcomes after Experimental Traumatic Brain Injury