Trends in Molecular Medicine
ReviewThe calpain family and human disease
Section snippets
The classic calpain 1 and calpain 2 (capn1, 2 and 4)
Human calpain 1 and 2 differ in their sensitivity to calcium in vitro: they are activated by low and high micromolar free Ca2+, respectively. Yet, both are heterodimeric proteins comprising a large 78–80-kDa catalytic subunit (encoded by capn1 and capn2, respectively) 3, 4 and a common 29-kDa regulatory subunit (encoded by capn4) 5 (Table 1). Recently, a gene encoding a highly homologous small subunit has been cloned (capn14) (Table 1). This subunit has fewer Gly repeats in its N-terminal
Non-EF-hand subfamily (calpain 5, 6, 7, 10 and 13)
Calpain 5 (htra-3) was initially identified as a homologue of the Caenorhabditis elegans sex determination gene tra-3. Recently, Sokol et al. elegantly demonstrated that another sex determinant protein, TRA-2A, is the probable endogenous proteolysis substrate for TRA-3 in C. elegans 24. It is not known whether a human homologue for TRA-2A exists or not. Calpain 5 mRNA appears to be present in multiple human tissues, including small intestine, colon, liver and testis 25. This suggests that
Calpain 1 and calpain 2 in acute neurological injuries and Alzheimer's disease
Ischemic strokes and traumatic brain injury. Glutamate doubles as a major excitatory amino acid in the CNS and as a neurotoxin (excitotoxin) when the synaptic glutamate concentration goes beyond the safety threshold. Cerebral ischemia (during strokes and cardiac arrest) and traumatic brain injury (TBI) represent the two most common and well-studied manifestations of in vivo excitotoxicity 32 and calpain activation (Box 1). Generally, in or near the core of ischemic or traumatic brain injury,
Perspective and future prospective
Calpain research has reached new heights with recent advances in both discovery of new calpain family members and the molecular understanding of the structure–function relationship of calpain 2. Continued refinement of selective and potent calpain1 and 2 inhibitors might find applications in neurological and neurodegenerative conditions and possibly human cataracts. Identification of relevant physiological substrate protein(s) for calpain 3, 9 and 10 seems to hold the key to understanding and
Outstanding questions
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How many more calpain genes are there in the human genome?
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What level of redundancy exists for mammalian calpains?
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What is the function of calpain 5 and is the related calpain 6, which lacks protease activity, has dominant-negative function opposing calpain 5?
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What is the key substrate(s) for calpain 9 and what is its relationship to gastric cancer?
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What is the key substrate(s) for calpain 10 and what is its relationship to type 2 diabetes?
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Does calpastatin have additional functions besides
Acknowledgements
We are grateful for the contributions from our colleagues R. Nath, S.Dutta, A. Probert, P-W.Yuen, N. Kupina, X.Ren, G. Schielke and E.Hall, Y. Sun and collaborators K.McGinnis, B. Pike, R.Hays, J. Inou and M.Azuma. We also apologize to many researchers whose relevant work we cannot cite owing to space restrictions.
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2020, Progress in Retinal and Eye ResearchCitation Excerpt :Calpains are a family of cytosolic cysteine proteases whose enzymatic activities are dependent on Ca2+, in the sense that while they are expressed in every cell, the calpains are not constitutively active but rather are activated in a number of steps by Ca2⁺ (Suzuki et al., 2004). To date, 15 calpain isoforms have been discovered in mammals and the calpain family can be subdivided into typical (calpain 1, 2, 3, 8, 9, 11, and 12) and atypical calpains (calpain 5, 6, 7, 8b, 10a, and 15) (Huang and Wang, 2001; Suzuki et al., 2004). Calpain isoforms have been implicated in cellular functions such as signal transduction, cell cycle, proliferation, differentiation, migration, apoptosis, membrane function, formation of muscle fibres, dendritic spine formation and pruning, and many others (Goll et al., 2003; Kanamori et al., 2013; Smalheiser and Lugli, 2009; Suzuki et al., 2004).