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Role of the Cysteine Proteases Calpain and Cathepsins

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Role of the Cysteine Proteases Calpain and Cathepsins Neuropathology 1999; 19, 356–365 Review Article Ischemic delayed neuronal death: Role of the cysteine proteases calpain and cathepsins Anton B Tontchev and Tetsumori Yamashima Department of Neurosurgery, Kanazawa University School of Medicine, Kanazawa, Japan A few days after a transient brain ischemia, the pyramidal (DND) and was first described in gerbils in 1982.1,2 Later, neurons in the cornu Ammonis (CA) 1 sector of the its clinical relevance was also confirmed.3,4 Both necrosis1–5 hippocampus undergo selective death, a process named and apoptosis have been reported as a type of cell death delayed neuronal death (DND). Cell death may occur as of DND, but its molecular mechanisms remain largely necrosis and/or apoptosis, and both have been reported to unclear.6,7 take place in DND. The cell’s decision between apoptosis The role of calcium (Ca2ϩ) in ischemic neuronal death is and necrosis may depend on the strength of the insult, the well recognized.8 An excessive postischemic Ca2ϩ mobi- balance of downstream signal transduction systems, and lization occurs in CA1 neurons9,10 by both glutamate- the expression level of pro- and anti-apoptotic or necrotic induced Ca2ϩ influx11,12 and/or inositol 1,4,5-trisphosphate 2؉ 2ϩ 13,14 factors. Cytosolic calcium (Ca ) overload specifically (IP3)-induced Ca release from intracellular stores. occurs in the CA1 neurons after ischemia and thus is Elevated intracellular Ca2ϩ concentration in turn activates considered a common triggering event of the death a series of enzymes including proteases, phospholipases, ؉ cascade. As Ca2 activates a wide array of intracellular phosphatases and protein kinases. It may also trigger the ؉ enzymes, many Ca2 -targeted enzymes have been im- synthesis of the free radical nitric oxide (NO), involved in plicated in DND. Among these, the present review will neuronal apoptosis.15 focus on the cysteine proteases calpain and cathepsins (B Among the Ca2ϩ-activated enzymes, the authors will and L). In addition, their possible interactions with another focus on the cysteine proteases calpain (EC 3.4.22.17) and family of cysteine proteases, caspases, will be discussed in cathepsins (particularly cathepsins B (EC 3.4.22.1) and relation to the cellular fate toward apoptosis or necrosis. L (EC 3.4.22.15)), because of the recent progress in understanding their role in the pathogenesis of DND.16–18 Key words: brain ischemia, calpain, cathepsin, delayed Calpain is a cytosolic cysteine protease ubiquitously and neuronal death. constitutively expressed in mammalian cells.19 Two forms of the enzyme are known: µ-calpain (calpain I) and m-calpain ϩ INTRODUCTION (calpain II). They differ in their sensitivity to Ca2 , µ- calpain being activated at a low (micromolar) Ca2ϩ Cerebral ischemia has profound effects on the brain, concentration, while m-calpain is activated at a higher inducing both immediate and delayed injuries. Even a (millimolar) Ca2ϩ concentration. Calpains are considered transient ischemic insult is sufficient to cause selective to participate in various intracellular signaling pathways damage to certain sensitive brain regions. The cornu mediated by Ca2ϩ. They are heterodimers, consisting of Ammonis (CA) 1 sector of the hippocampus is considered 30 and 80 kDa subunits. The small subunits are identical such a region, since a transient global ischemia is able to among one and the same tissue and/or animal species, while cause neuronal death a few days after cerebral ischemia. the large subunits are similar but not identical. A very This phenomenon is designated as delayed neuronal death specific endogenous inhibitor, calpastatin, which interacts with the Ca2ϩ-binding domains of both large and small subunits, inhibits calpain. The coexistence of calpain and calpastatin in cells suggests a pivotal role of this inhibitor in Correspondence: Tetsumori Yamashima, MD, PhD, Department the regulation of calpain activity.20 of Neurosurgery, Kanazawa University School of Medicine, 13-1 Like calpains, cathepsins also belong to the papain Takaramachi, Kanazawa, 920-8641, Japan. Email: yamashim@med. 21 kanazawa-u.ac.jp superfamily of cysteine proteases. They are synthesized as Received 30 August 1999; accepted 9 September 1999. inactive precursors and require proteolytic activation that Cysteine proteases in neuronal death 357 generally requires an acidic pH. Thus, they are localized Table 1 A list of selected calpain substrates predominantly to the lysosomes (cathepsins B, H, L, S, C Substrate Reference and K), but also to the nucleus (cathepsins B and L) and 22 Cytoskeletal proteins cytosol (cathepsins B and E). Most cathepsins have Tropomyosin 20 molecular weight (MW) values of 20–35 kDa (with the Actin 23 exception of cathepsin C, which is approximately 200 kDa). Spectrin 24, 25 Unlike calpains, they lack Ca2ϩ-binding domains. NF-68 26 Tubulin 20 Numerous cathepsin inhibitors exist, the most abundant of Tau 27 which are the cystatins. The latter interact with active Ca2ϩ-binding proteins proteases to bind them tightly and essentially irreversibly. Caldesmon 34 Their function is to inhibit cathepsins that escape Calponin 34 Enzymes compartmentalization and protect cells, tissues and the Calpastatin 35 circulation from unwarranted cysteine protease activity.21 Nitric oxide synthase 36 PKC 20 Calcineurin 20 SUBSTRATES OF CALPAIN AND Growth factor/cytokine receptors CATHEPSIN EGF receptor 28 PDGF receptor 20 The ubiquitous and constitutive expression of µ- and Transcription and translation factors m-calpains makes it difficult to precisely define their AP-1 (c-Fos/c-Jun) 29 c-Myc 29 physiological functions. A large number of calpain sub- CREB 29 strates have been demonstrated, mainly in vitro, including eIF-4E 30 cytoskeletal proteins,20,23–27 growth factor receptors,20,28 and Cell cycle/tumor suppressor proteins transcription- and cell cycle-related proteins29–33 (Table 1). Cyclin D1 31 p53 32 In relation to the latter, selective nuclear transport of NF2 (merlin, schwannomin) 33 µ-calpain has been demonstrated.38 NF-68, neurofilament 68 kDa protein; PKC, protein kinase C; EGF, It is worth noting that calpastatin itself is also a target epidermal growth factor; PDGF, platelet-derived growth factor;AP-1, of calpain,35 and µ-calpain is capable of activating m- activator protein-1; CREB, cyclic AMP response element-binding calpain.37 Thus, a calpain cascade may coordinate the protein; eIF-4E, eukaryotic initiation factor-4E; c-Myc, c-myelocytoma oncogene product. functions of calpains in cells. A variety of calpain functions have been proposed including intracellular protein deg- radation, platelet aggregation, erythrocyte aging, neu- trophil activation as well as long-term potentiation in the hippocampus. Detailed data on the physiological functions of calpains are available in other reviews.19–21 Cathepsins were shown to participate in the extracel- lular matrix remodeling, and cathepsin K is considered the most potent elastolytic enzyme known.21 Collagen cleavage by cathepsin B39 and fibronectin degradation by cathepsin D40 have been demonstrated. Several cytoskeletal proteins are substrates of cathepsin D including myelin basic protein,41 neurofilament proteins,42 microtubule-associated protein 2,43 tubulin43 and -amyloid protein.44 Cathepsins are essential for the generation of antigenic peptides in the major histocompatibility complex class II antigen presenta- tion (cathepsin S)21 as well as for the processing of prohor- mone molecules, such as pro-endothelin-1 (cathepsin D)45 and prorenin (cathepsin B).46 Cathepsin B is also capable of cleaving the myristoylated alanine-rich C kinase sub- 2ϩ Fig. 1 Time course of [Ca ]i elevation in the monkey strate (MARCKS),47 a major cellular substrate of protein hippocampal slice during hypoxia–hypoglycemia (adapted 2ϩ kinase C. from Fig. 7a of Reference 16). The largest [Ca ]i elevation demonstrated by relative fluorescence intensity was observed Cathepsin L has been implicated in tumor progression ᭝ 2ϩ 21,22 preferentially in the CA1 sector ( ), in contrast to the [Ca ]i and bone resorption. Interestingly, members of the elevation in the CA3, CA4 and the dentate gyrus (a summing caspase (the other major cysteine protease) superfamily, graph shown by (᭺)). 358 AB Tontchev and T Yamashima 2ϩ 16 namely caspase-11 and to a lesser extent caspase-1, have ([Ca ]i) during hypoxia–hypoglycemia. The area of 48 2ϩ recently been shown to be substrates of cathepsin B, while the maximum [Ca ]i elevation in the slice (Fig. 1) was caspase-3 has been shown to be a substrate of cathepsin L.49 selectively localized to the CA1 sector, the area of DND in These data, together with the observation of caspase- vivo. In previous studies, indirect evidence of Ca2ϩ-induced mediated calpastatin degradation,50 suggest a potential calpain involvement in DND has been demonstrated interaction between the caspase and papain superfamilies by the finding of calpain-mediated fodrin degradation, in integrating their cellular effects. associated with Ca2ϩ-induced calpain activation in CA1 neurons after brain ischemia.24 Using an antibody that specifically reacts with an activated form of µ-calpain51 and CALPAIN AND CATHEPSIN a primate model of 20-min whole-brain complete ischemia, INVOLVEMENT IN ISCHEMIC DELAYED Yamashima et al. provided direct evidence of calpain NEURONAL DEATH activation prior to DND.16 At immunohistochemistry, the Analyzing postischemic neuronal Ca2ϩ mobilization by perikarya of CA1 neurons, immediately after the ischemic an in vitro ischemia experiment using acute hippocampal insult, showed a specific staining of activated µ-calpain slices, Yamashima et al. measured intracellular free Ca2ϩ (Fig. 2a,b) as compared with both the controls and the Fig. 2 Calpain in ischemic hippocampus. (a,b) Immunohistochemistry using anti-activated µ-calpain antibody. A significant increase in immunoreactivity is observed in ischemic CA1 neurons (b) compared with controls (a) showing no staining (ϫ700; bar ϭ 10 µm. (c) Western blot analysis of control (C) and postischemic (I) hippocampal sectors using antibodies against inactive (pre-µ, upper half) or activated (post-µ, lower half) µ-calpain.
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