Calpain activation and α-spectrin cleavage in rat brain by ethanol

Rajgopal, Yadavalli; Vemuri, Mohan C.

doi:10.1016/s0304-3940(02)00063-0

Cited by 37 publications

(27 citation statements)

References 18 publications

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“…Mitochondrial inhibition by 3-nitropropionic acid may lead to initiation of oxidative stress and calpain-mediated spectrin proteolysis [72], but administration of calpain inhibitors shifted the cell death morphology from necrosis towards apoptosis [73], which is in agreement with the calpain-caspase cross-talk hypothesis (see below). Enhanced calpain activity combined with increased cleavage of aII-spectrin was also observed in alcoholic neurodegeneration [74] and methylmercury treatment of cortical neurons [75], with a possible role of NMDA receptors in the latter. With respect to the data presented, potential artifactual calpain activation should be considered.…”

Section: Excitotoxicity and Effects Of Toxinsmentioning

confidence: 78%

Spectrin and calpain: a ‘target’ and a ‘sniper’ in the pathology of neuronal cells

Czogalla

Sikorski

2005

Cell. Mol. Life Sci.

177

144

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It is well documented that activation of calpain, a calcium-sensitive cysteine protease, marks the pathology of naturally and experimentally occurring neurodegenerative conditions. Calpain-mediated proteolysis of major membrane-skeletal protein, alphaII-spectrin, results in the appearance of two unique and highly stable breakdown products, which is an early event in neural cell pathology. This review focuses on spectrin degradation by calpain within neurons induced by diverse conditions, emphasizing a current picture of multi-pattern neuronal death and a recent success in the development of spectrin-based biomarkers. The issue is presented in the context of the major structural and functional properties of the two proteins.

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Section: Excitotoxicity and Effects Of Toxinsmentioning

confidence: 78%

Spectrin and calpain: a ‘target’ and a ‘sniper’ in the pathology of neuronal cells

Czogalla

Sikorski

2005

Cell. Mol. Life Sci.

177

144

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“…␣II spectrin has a -calpain cleavage site based on the secondary and tertiary conformational features surrounding the cleavage site, rather than the linear sequence (49). Activated calpain cleaves spectrin and generates 145-and 150-kDa fragments, recognized by a specific antibody (50). It has been reported that calpain-cleaved fragments of ␣-spectrin are a hallmark of hyperactivation of the calcium-calpain system (51), and injection of 6-hydroxydopamine into rodent brains resulted in calpain activation and the cleavage of ␣-spectrin.…”

Section: Discussionmentioning

confidence: 99%

Calcium-activated Calpain-2 Is a Mediator of Beta Cell Dysfunction and Apoptosis in Type 2 Diabetes

Huang

Gurlo

Haataja

et al. 2010

Journal of Biological Chemistry

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The islet in type 2 diabetes (T2DM) and the brain in neurodegenerative diseases share progressive cell dysfunction, increased apoptosis, and accumulation of locally expressed amyloidogenic proteins (islet amyloid polypeptide (IAPP) in T2DM). Excessive activation of the Ca 2؉ -sensitive protease calpain-2 has been implicated as a mediator of oligomer-induced cell death and dysfunction in neurodegenerative diseases. To establish if human IAPP toxicity is mediated by a comparable mechanism, we overexpressed human IAPP in rat insulinoma cells and freshly isolated human islets. Pancreas was also obtained at autopsy from humans with T2DM and nondiabetic controls. We report that overexpression of human IAPP leads to the formation of toxic oligomers and increases beta cell apoptosis mediated by increased cytosolic Ca 2؉ and hyperactivation of calpain-2. Cleavage of ␣-spectrin, a marker of calpain hyperactivation, is increased in beta cells in T2DM. We conclude that overactivation of Ca 2؉ -calpain pathways contributes to beta cell dysfunction and apoptosis in T2DM. Hyperglycemia in type 2 diabetes mellitus (T2DM)3 is due to impaired insulin secretion in the setting of relative insulin resistance (1). The islets of Langerhans in T2DM are characterized by a deficit in beta cells, increased beta cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP), a 37-amino acid highly conserved peptide co-expressed and secreted with insulin by pancreatic beta cells (2, 3).The pathology of the islet in T2DM and brain in neurodegenerative diseases such as Alzheimer disease share several parallels. In both, the loss of functional tissue is associated with deposition of a locally expressed protein with the potential to form amyloid fibrils (Alzheimer beta protein in Alzheimer disease and IAPP in T2DM) (2, 4). In both T2DM and Alzheimer disease, there has been a debate as to whether the amyloid deposits contribute to cell loss (the so-called amyloid hypothesis) or are secondary to the processes leading to cell loss. Evidence against a direct role of amyloid deposits on cell loss is the poor correlation between the extent of amyloid deposits and the severity of disease in both human and animal models (3,5,6). Moreover, preformed amyloid fibrils are not cytotoxic when applied to cells (7).However, several lines of evidence are supportive of a role of cytotoxicity by amyloidogenic proteins. These include genetic predisposition in occasional families with mutations leading to increased amyloidogenicity of the amyloid protein (8) and reproduction of the disease phenotype in rodent models transgenic for the relevant human amyloidogenic protein (9). There is an increasing appreciation that the cytotoxic forms of amyloidogenic proteins are small nonfibrillar oligomers that may form in membranes and cause nonselective membrane permeability (7, 10, 11), the toxic oligomer hypothesis. Moreover, misfolding and aggregation of amyloidogenic proteins into toxic oligomers induce apoptosis through the mechanism of endoplasmic retic...

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“…In animal models, chronic alcohol treatment is associated with neuronal loss in hippocampal formation and basal forebrain [7]. Recent studies [8][9][10] have reported cytochrome c release [8,9], activation of m-calpain [9,10] after chronic ethanol treatment. Chronic alcohol administration leads to induction of apoptosis [8] mechanisms of cell death may differ.…”

Section: Introductionmentioning

confidence: 99%

Cell Death is Associated with Reduced Base Excision Repair During Chronic Alcohol Administration in Adult Rat Brain

2008

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The cell death cascades in different brain regions namely hippocampus and frontal cortex of rats fed with 10% (v/v) ethanol for 12 weeks, was examined. After Western blotting, different cell death associated proteins displayed differential activation in the two regions observed. In hippocampus, activated caspase-3 and caspase-7 resulted in subsequent cleavage of poly(ADP-ribose) polymerase-1 (PARP-1). Cytochrome c release to cytosol and apoptosis inducing factor (AIF) translocation to nucleus was marginal. B-cell leukemia/lymphoma-2 (Bcl-2) translocation to cytosol was significant whereas Bcl-2-associated X protein (Bax) and Bcl-associated death protein (Bad) were largely located in cytosol. Further, upregulation of N-methyl D-aspartate receptor subunit 1 (NMDAR1), N-methyl D-aspartate receptor subunit 2B (NMDAR2B), N-methyl D-aspartate receptor subunit 2C (NMDAR2C) and activation of calpains were observed. In frontal cortex, caspase-3 activation, cleavage of PARP-1 and nuclear translocation of AIF were more pronounced. Moreover, cytochrome c release to cytosol, Bcl-2 translocation to cytosol was evident. However, levels of Bax, Bad, NMDA receptor subunits, and calpains were unaffected. Apoptosis was further substantiated by in situ staining for terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL). Results of the current study revealed that frontal cortex exhibits a higher level of ethanol-induced apoptosis relative to hippocampus. DNA polymerase beta assay and immunoblot showed significant loss in base excision repair in ethanol treated group.

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Calpain activation and α-spectrin cleavage in rat brain by ethanol

Cited by 37 publications

References 18 publications

Spectrin and calpain: a ‘target’ and a ‘sniper’ in the pathology of neuronal cells

Spectrin and calpain: a ‘target’ and a ‘sniper’ in the pathology of neuronal cells

Calcium-activated Calpain-2 Is a Mediator of Beta Cell Dysfunction and Apoptosis in Type 2 Diabetes

Cell Death is Associated with Reduced Base Excision Repair During Chronic Alcohol Administration in Adult Rat Brain

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