Trends in Neurosciences
ReviewCalpain and caspase: can you tell the difference?
Section snippets
Apoptosis and necrosis in neurological and neurodegenerative disorders
About five years ago, it was generally accepted that acute degenerative neuronal death, such as that seen in cerebral ischemia, traumatic brain injury (TBI) and spinal-cord injury (SCI) were necrotic in nature. Linnik and colleagues were the first to challenge this idea by showing evidence for apoptosis in a rat focal-ischemia model (defined by the presence of DNA laddering)2. Since then, numerous reports have documented similar findings in either global ischemia or excitotoxicity models3, 4.
Calpain in necrotic death
Over the past decade, the significant focus of research was on calpain-mediated proteolysis, and its contribution to necrotic neuronal death in ischemic and excitotoxic neuronal injury13. The two ubiquitous calpains m- and μ-calpain) exist as a pro-enzyme heterodimer (80 kDa–29 kDa) in resting cells but this is activated by Ca2+ and autolytic processing (to produce a heterodimer 78 kDa–18 kDa; Table 1). Physiologically, the activity of these calpains might also be regulated by the endogenous
Caspases in apoptosis
The discovery that a protein required for apoptosis in the nematode, Caenorhabditis elegans, CED-3 is homologous to the mammalian interleukin-1β-converting enzyme (ICE) led to the discovery of a large number of ICE-like proteases (renamed caspases) and their roles as mediators of apoptosis in a wide range of the cell types17. Caspase 3 (previously called CPP32) is of particular interest as it appears to be a common downstream apoptosis effector. It exists as proenzyme (pro-caspase 3) in most
Calpain is also activated in some apoptosis systems
Calpain activation in any form of apoptosis was first demonstrated in thymocytes, as measured by calpain autolysis27. In addition, various calpain inhibitors were found to protect against apoptosis in immune cells27, 28. This finding was then extended to show that calpain was indeed activated in staurosporine-treated neuroblastoma SH-SY5Y cells, in NGF-deprived rat PC12 cells and in low-K+-treated rat cerebellar granule neurons14, 29. These data were obtained primarily by detection of calpain
Distinct α-spectrin breakdown patterns generated by calpain and caspase: diagnostic markers for neuronal apoptosis versus necrosis
Non-erythroid α-spectrin (also called α-fodrin) is degraded to a 120 kDa fragment, spectrin breakdown product 120 (SBDP120) in apoptotic neurons but not in necrotic neurons14. Yet, calpain-mediated α-spectrin breakdown to a 150 kDa and 145 kDa doublet is not only present in necrotic neuronal death, but also in most forms of neuronal apoptosis14, 29, 34 (Fig. 1). In contrast, caspase-mediated formation of SBDP120 (and also caspase-specific SBDP150) occurs exclusively in neuronal apoptosis25, 34,
Other common or related substrates for caspase 3 and calpain
The vulnerability of non-erythroid α-spectrin to proteolysis in both necrosis and apoptosis suggests that the proteolysis mediated by the caspase and calpain systems might have some common roles in mediating cell death. In apoptosis, proteolysis is likely to be important in suspending cell function by disabling a number of enzymes involved in signal transduction, which disables the mechanisms that allow the cell to repair its DNA or to go through the cell cycle, and degrades its cytoskeleton
Two proteases: two forms of neuronal death
In this article, the role of two cytosolic cysteine proteases (calpain and caspase 3) in two forms of neuronal death (necrosis and apoptosis) has been highlighted (Table 1). On the basis of genetic data and the elucidation of the apoptosis cascade, it is apparent that caspase has a central role in transducing the apoptosis signal. Caspase-3 activation is a unique feature of apoptosis. By contrast, necrotic cell death is, almost without exception, associated with massive Na+ and Ca2+ influxes
Acknowledgements
The author thanks his co-workers, past and present (including Kim McGinnis, Rathna Nath, Rand Posmantur and Iradj Hajimohammadreza) and his collaborators Ronald Hayes and Margaret Gnegy for their original contributions. With apologies to the many researchers whose work was not cited owing to limited space.
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