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.
References (76)
Global ischemia can cause DNA fragmentation indicative of apoptosis in rat brain
Neurosci. Lett.
(1993)Neuronal cell death, a demise with different shapes
Trends Pharmacol. Sci.
(1999)- et al.
Calpain, a protease in search of a function?
Biochem. Biophys. Res. Commun.
(1998) - et al.
Caspases, killer proteases
Trends Biochem. Sci.
(1997) Identification and mapping of Casp7, a cysteine protease resembling CPP32 beta, interleukin-1β converting enzyme, and CED 3
Genomics
(1997)Protease involvement in fodrin cleavage and phosphatidylserine exposure in apoptosis
J. Biol. Chem.
(1996)Constitutive apoptosis in human neutrophils requires synergy between calpains and the proteasome downstream of caspases
J. Biol. Chem.
(1998)Simultaneous degradation of αII- and βII-spectrin by caspase 3 (CPP32) in apoptotic cells
J. Biol. Chem.
(1998)Proteolysis of fodrin (non-erythroid spectrin) during apoptosis
J. Biol. Chem.
(1995)Caspase 3 is required for α-fodrin cleavage but dispensable for cleavage of other death substrates in apoptosis
J. Biol. Chem.
(1998)
Lens Ca2+ activated proteinase, degradation of vimentin
Biochem. Biophys. Res. Commun.
Rapid fragmentation of vimentin in human skin fibroblasts exposed to tamoxifen, a possible involvement of caspase 3
Biochem. Biophys. Res. Commun.
Apoptosis-associated proteolysis of vimentin in human prostate epithelial tumor cells
Biochem. Biophys. Res. Commun.
Purification and characterization of calpains from pig epidermis and their action on epidermal keratin
J. Invest. Dermatol.
Apoptosis generates stable fragments of human type I keratins
J. Biol. Chem.
Identification of actin as a substrate of ICE and an ICE-like protease and involvement of an ICE-like protease but not ICE in VP-16-induced U937 apoptosis
Biochem. Biophys. Res. Commun.
Degradation of actin and vimentin by calpain II, a Ca2+-dependent cysteine proteinase, in bovine lens
FEBS Lett.
Different cleavage pattern for poly(ADP-ribose) polymerase during necrosis and apoptosis in HL-60 cells
Biochem. Biophys. Res. Commun.
Isolation and identification of a proteinase from calf thymus that cleaves poly(ADP-ribose) polymerase and histone H1
Biochim. Biophys. Acta.
Pro-caspase-3 and poly(ADP)ribose polymerase (PARP) are calpain substrates
Biochem. Biophys Res. Commun.
Ca2+/calmodulin-dependent protein kinase IV is cleaved by caspase 3 and calpain in SH-SY5Y human neuroblastoma cells undergoing apoptosis
J. Biol. Chem.
Cleavage of focal adhesion kinase by caspases during apoptosis
J. Biol. Chem.
Involvement of caspases in proteolytic cleavage of Alzheimer’s amyloid-β precursor protein and amyloidogenic Aβ peptide formation
Cell
Limited proteolysis of protein kinase C subspecies by Ca2+-dependent neutral protease (calpain)
J. Biol. Chem.
Caspase 3-mediated cleavage of protein kinase C theta in induction of apoptosis
J. Biol. Chem.
Endogenous cleavage of phospholipase Cβ3 by agonist-induced activation of calpain in human platelets
J. Biol. Chem.
Caspase-mediated fragmentation of calpain inhibitor protein calpastatin during apoptosis
Arch. Biochem. Biophys.
Mice deficient in IL-1 beta-converting enzyme are defective in production of mature IL-1 beta and resistant to endotoxic shock
Cell
Apoptosis, oncosis, and necrosis. An overview of cell death
Am. J. Pathol
Evidence supporting a role for programmed cell death in focal cerebral ischemia in rats
Stroke
DNA fragmentation in rat brain after intraperitoneal administration of kainite
NeuroReport
Apoptosis and necrosis, two distinct events induced, respectively, by mild and intense insults with N-methyl-d-aspartate or nitric oxide/superoxide in cortical cell cultures
Proc. Natl. Acad. Sci. U. S. A
Evidence of apoptotic cell death after experimental traumatic brain injury in the rat
Am. J. Pathol.
Apoptosis after traumatic human spinal cord injury
J. Neurosurg.
Regional variability in DNA fragmentation after global ischemia evidenced by combined histological and gel electrophoresis observations in the rat brain
J. Neurochem.
Evidence for activation of caspase 3-like protease in excitotoxin- and hypoxia/hypoglycemia-injured neurons
J. Neurochem.
Mechanisms of cell death induced by the mitochondrial toxin 3-nitropropionic acid, acute excitotoxic necrosis and delayed apoptosis
J. Neurosci.
Cytoskeletal breakdown and apoptosis elicited by NO donors in cerebellar granule cells require NMDA receptor activation
J. Neurochem.
Cited by (821)
Comparison of oxidative stress-mitochondria-mediated tenderization in two different bovine muscles during aging
2022, Food Chemistry: Molecular SciencesS-acylation regulates the membrane association and activity of Calpain-5
2022, Biochimica et Biophysica Acta - Molecular Cell ResearchThe Calpain Proteolytic System
2022, Encyclopedia of Cell Biology: Volume 1-6, Second Edition