The calpains

Melloni, Edon; Pontremoli, S.

doi:10.1016/0166-2236(89)90093-3

Cited by 181 publications

(119 citation statements)

References 44 publications

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“…A family of nonlysosomal calcium-activated neutral cysteine proteases, referred to as calpain family (-and m-calpain isoforms in the present study), has been mechanistically implicated in the regulation of various cellular functions (5,6). Because multiple lines of evidence indicate that neuronal cytoskeletal constituents, including microtubule-associated proteins (MAPs), 1 neurofilaments, spectrin, and actin, are preferred substrates for calpain (7)(8)(9)(10)(11), calpain is likely to play essential roles in the pathophysiological derangement of cytoskeletons.…”

mentioning

confidence: 99%

Distinct Mechanistic Roles of Calpain and Caspase Activation in Neurodegeneration as Revealed in Mice Overexpressing Their Specific Inhibitors

Higuchi

Tomioka

Takano

et al. 2005

Journal of Biological Chemistry

148

127

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Enzymatic proteolysis has been implicated in diverse neuropathological conditions, including acute/subacute ischemic brain injuries and chronic neurodegeneration such as Alzheimer disease and Parkinson disease. Calcium-dependent proteases, calpains, have been intensively analyzed in relation to these pathological conditions, but in vivo experiments have been hampered by the lack of appropriate experimental systems for a selective regulation of the calpain activity in animals. Here we have generated transgenic (Tg) mice that overexpress human calpastatin, a specific and the only natural inhibitor of calpains. In order to clarify the distinct roles of these cell death-associated cysteine proteases, we dissected neurodegenerative changes in these mice together with Tg mice overexpressing a viral inhibitor of caspases after intrahippocampal injection of kainic acid (KA), an inducer of neuronal excitotoxicity. Immunohistochemical analyses using endo-specific antibodies against calpain-and caspase-cleaved cytoskeletal components revealed that preclusion of KA-induced calpain activation can rescue the hippocampal neurons from disruption of the neuritic cytoskeletons, whereas caspase suppression has no overt effect on the neuritic pathologies. In addition, progressive neuronal loss between the acute and subacute phases of KA-induced injury was largely halted only in human calpastatin Tg mice. The animal models and experimental paradigm employed here unequivocally demonstrate their usefulness for clarifying the distinct contribution of calpain and caspase systems to molecular mechanisms governing neurodegeneration in adult brains, and our results indicate the potentials of specific calpain inhibitors in ameliorating excitotoxic neuronal damages.Diverse proteolytic enzymes have been indicated to mediate molecular processes of neurodegeneration (1) because axonal, dendritic, and synaptic integrity is targeted by protease activities provoked by different types of insults (2-4). A family of nonlysosomal calcium-activated neutral cysteine proteases, referred to as calpain family (-and m-calpain isoforms in the present study), has been mechanistically implicated in the regulation of various cellular functions (5, 6). Because multiple lines of evidence indicate that neuronal cytoskeletal constituents, including microtubule-associated proteins (MAPs), 1 neurofilaments, spectrin, and actin, are preferred substrates for calpain (7-11), calpain is likely to play essential roles in the pathophysiological derangement of cytoskeletons. Acute and subacute brain insults such as traumatic injury and hypoxia/ ischemia involve prominent calpain activation evoked by calcium dysregulation in neurons. Moreover, several independent studies have highlighted the elevation of calpain activity in chronic neurodegenerative disorders including Alzheimer disease (12, 13) and Parkinson disease (14). However, it remains unclear whether the relationship between calpain activation and the disorganization of the neuronal cytoskeletons in these pathologies...

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mentioning

confidence: 99%

Distinct Mechanistic Roles of Calpain and Caspase Activation in Neurodegeneration as Revealed in Mice Overexpressing Their Specific Inhibitors

Higuchi

Tomioka

Takano

et al. 2005

Journal of Biological Chemistry

148

127

View full text Add to dashboard Cite

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“…To date, two isoforms of calpain have been identified: calpain I (or -calpain) and calpain II (or m-calpain), which require, respectively, low and high micromolar concentrations of calcium for their activation. 3,4 After activation by calcium, calpain cleaves a specific subset of cellular proteins. For instance, activation of calpain I leads to the degradation of IB (IB␣ or IB␤) in the proteasome and, hence, is an essential step in the translocation of NF-B from the cytosol into the nucleus.…”

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confidence: 99%

Calpain Inhibitor I Reduces the Development of Acute and Chronic Inflammation

Cuzzocrea

McDonald

Mazzon

et al. 2000

The American Journal of Pathology

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There is limited evidence that inhibition of the activity of the protease calpain I reduces inflammation. Here we investigate the effects of calpain inhibitor I in animal models of acute and chronic inflammation (carrageenan-induced pleurisy and collagen-induced arthritis). We report here for the first time that calpain inhibitor I (given at 5, 10, or 20 mg/kg i. It is now widely accepted that the formation of pro-inflammatory cytokines [eg, tumor ecrosis factor-␣ (TNF␣), interleukin IL)Ϫ1, IL-6,or IL-8], the expression on endothelium and neutrophils of adhesion molecules (eg, VCAM-1, ICAM-1), and the overproduction of vasoactive mediators [eg, nitric oxide (NO) by inducible NO synthase (iNOS) or eicosanoids by cyclooxygenase-2 (COX-2)] play important roles in the pathophysiology of inflammation. The expression of inducible genes leading to the formation of these proteins relies on transcription factors, which are controlled by (other) inducible genes and, hence, require de novo protein synthesis or alternatively by so-called primary transcription factors. Among the latter, nuclear factor B (NF-B) has received a considerable amount of attention because of its unique mechanism of activation and its active role in cytoplasmic/nuclear signaling, and its rapid response to pathogenic stimulation of NF-B plays a central role in the regulation of many genes responsible for the generation of mediators or proteins in inflammation. These include the genes for TNF␣, IL-1, IL-6, IL-8, VCAM-1, ICAM-1, iNOS, and COX-2, to name but a few.

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“…Along with other major cytoskel etal proteins, spectrin is a preferred substrate for calpain-a class of calcium-dependent cysteine pro teases widely present in many tissues (Melloni and Pontremoli, 1989;Siman et aI., 1984) and found in neurons and glia near cytoskeletal elements (Perl mutter et aI., 1988(Perl mutter et aI., , 1990)-a location possibly re lated to their role in synaptic plasticity. At least two isozymes of calpain are known, which differ mark edly in their calcium requirement.…”

Section: Discussionmentioning

confidence: 99%

“…At least two isozymes of calpain are known, which differ mark edly in their calcium requirement. Cal pain I (mu cal pain) is activated at micro molar concentrations of calcium, whereas calpain II requires millimolar concentrations (Melloni and Pontremoli, 1989;Siman et aI., 1984).…”

Section: Discussionmentioning

confidence: 99%

Local Cerebral Glucose Utilization and Cytoskeletal Proteolysis as Indices of Evolving Focal Ischemic Injury in Core and Penumbra

Yao

Ginsberg

Eveleth

et al. 1995

J Cereb Blood Flow Metab

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Summary:To ascertain the tempo of progression to irre versible injury in focal ischemia, we subjected halothane anesthetized Sprague-Dawley rats to photochemically in duced distal middle cerebral artery occlusion (dMCAO) combined with permanent ipsilateral and 1 h contralateral common carotid artery occlusions. Head temperature was maintained at 36°C. At times centered at either 1.5 or 3 h post-dMCAO, the rate of local glucose metabolism (lCMRgl) was measured by 2-deoxyglucose autoradiogra phy, and cytoskeletal proteolysis was assessed regionally by an immunoblotting procedure to detect spectrin break down products. At 1.5 h (n = 5), the cortical ischemic core was already severely hypometabolic (lCMRg1 15.5 ::t 10.8 J.l.moll00 g-I min -I, mean ::t SD), whereas the cor tical penumbral zone was hypermetabolic (69.0 ::t 9.7). (The lumped constant was verified to be unchanged by methylglucose studies.) Neutral red pH studies at this time point showed that both the core and penumbral Experimental successes in elucidating the patho physiology of cerebral ischemia and in developing effective strategies to reduce ischemic injury have made it incumbent to understand the time frame within which tissue progression to irreversible in jury occurs. Recent interest in this regard has fo cused on the means of defining and characterizing Received June 9, 1994; final revision received September 2, 1994; accepted October 17, 1994. 398zones were equally acidotic. By 3 h post-dMCAO (n = 6), ICMRgI in the penumbral zone had fallen to low levels (15.4 ::t 2.2 J.l.mol 100 g-I min-I) equal to those of the ischemic core (16.7 ::t 4.5). Correspondingly, spectrin breakdown in the ischemic core was advanced at both 2 and 3.5 h post-dMCAO (36 ::t 18% and 33 ::t 18% of total spectrin, respectively), whereas in the penumbral zone spectrin breakdown was less extensive and more highly variable at both times (22 ::t 23% and 29 ::t 16%). We conclude that irreversible deterioration of the ischemic core, as evidenced by the onset of local cytoskeletal pro teolysis, begins within 2 h of middle cerebral artery oc clusion. In the ischemic penumbra, the transition from glucose hyper-to hypometabolism occurs by 3.5 h and is associated with a milder and more variable degree of spectrin breakdown.

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The calpains

Cited by 181 publications

References 44 publications

Distinct Mechanistic Roles of Calpain and Caspase Activation in Neurodegeneration as Revealed in Mice Overexpressing Their Specific Inhibitors

Distinct Mechanistic Roles of Calpain and Caspase Activation in Neurodegeneration as Revealed in Mice Overexpressing Their Specific Inhibitors

Calpain Inhibitor I Reduces the Development of Acute and Chronic Inflammation

Local Cerebral Glucose Utilization and Cytoskeletal Proteolysis as Indices of Evolving Focal Ischemic Injury in Core and Penumbra

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