The calpain family and human disease

doi:10.1016/S1471-4914(01)02049-4

Trends in Molecular Medicine

Volume 7, Issue 8, 1 August 2001, Pages 355-362

https://doi.org/10.1016/S1471-4914(01)02049-4 Get rights and content

Abstract

The number of mammalian calpain protease family members has grown to 14 on last count. Overactivation of calpain 1 and calpain 2 (and their small subunit) has long been tied to acute neurological disorders (e.g. stroke and traumatic brain injury) and recently to Alzheimer's disease. Loss-of-function mutations of the calpain 3 gene have now been identified as the cause of limb-girdle muscular dystrophy 2A. Calpain 10 was recently identified as a susceptibility gene for type 2 diabetes, whereas calpain 9 appears to be a gastric cancer suppressor. This review describes our current understanding of the calpain family members and their mechanistic linkages to the aforementioned diseases as well as other emerging pathological conditions.

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

•
How many more calpain genes are there in the human genome?
•
What level of redundancy exists for mammalian calpains?
•
What is the function of calpain 5 and is the related calpain 6, which lacks protease activity, has dominant-negative function opposing calpain 5?
•
What is the key substrate(s) for calpain 9 and what is its relationship to gastric cancer?
•
What is the key substrate(s) for calpain 10 and what is its relationship to type 2 diabetes?
•
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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Citation 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).
The cellular mechanisms underlying hereditary photoreceptor degeneration are still poorly understood, a problem that is exacerbated by the enormous genetic heterogeneity of this disease group. However, the last decade has yielded a wealth of new knowledge on degenerative pathways and their diversity. Notably, a central role of cGMP-signalling has surfaced for photoreceptor cell death triggered by a subset of disease-causing mutations.
In this review, we examine key aspects relevant for photoreceptor degeneration of hereditary origin. The topics covered include energy metabolism, epigenetics, protein quality control, as well as cGMP- and Ca²⁺-signalling, and how the related molecular and metabolic processes may trigger photoreceptor demise. We compare and integrate evidence on different cell death mechanisms that have been associated with photoreceptor degeneration, including apoptosis, necrosis, necroptosis, and PARthanatos. A special focus is then put on the mechanisms of cGMP-dependent cell death and how exceedingly high photoreceptor cGMP levels may cause activation of Ca²⁺-dependent calpain-type proteases, histone deacetylases and poly-ADP-ribose polymerase. An evaluation of the available literature reveals that a large group of patients suffering from hereditary photoreceptor degeneration carry mutations that are likely to trigger cGMP-dependent cell death, making this pathway a prime target for future therapy development.
Finally, an outlook is given into technological and methodological developments that will with time likely contribute to a comprehensive overview over the entire metabolic complexity of photoreceptor cell death. Building on such developments, new imaging technology and novel biomarkers may be used to develop clinical test strategies, that fully consider the genetic heterogeneity of hereditary retinal degenerations, in order to facilitate clinical testing of novel treatment approaches.

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Trends in Molecular Medicine

ReviewThe calpain family and human disease

Abstract

Section snippets

The classic calpain 1 and calpain 2 (capn1, 2 and 4)

Non-EF-hand subfamily (calpain 5, 6, 7, 10 and 13)

Calpain 1 and calpain 2 in acute neurological injuries and Alzheimer's disease

Perspective and future prospective

Outstanding questions

Acknowledgements

J. Biol. Chem.

J. Biol. Chem.

Biochemistry

Nature

EMBO. J.

Proc. Natl. Acad. Sci. U. S. A.

Nat. Struct. Biol.

Trends Neurosci.

Curr. Eye Res.

Methods Mol. Biol.

Biol. Chem.

Jpn. J.Cancer Res.

Genomics

Biochem. J.

Nat. Genet.

Trends Pharmacol. Sci.

J. Biol. Chem.

Prog. Neurobiol.

Stroke

J.Neurotrauma , 964

Brain Res.

Brain Res. Brain Res. Rev.

Exp. Eye Res.

Exp. Eye Res.

FEBS Lett.

Biochim. Biophys. Acta

Curr. Eye Res.

Biochem. Biophys. Res. Commun.

Biochim. Biophys. Acta

Nat. Med.

Biochim. Biophys. Acta

Int. J. Cancer

J. Biol. Chem.

Review
The calpain family and human disease