Calpains

Calpain-10 (CAPN10) is the fust diabetes gene to have been identified through a genome scan. The discovery of calpain-10 has identified it as a molecule of importance to insulin signaling and secretion that may have relevance to the fiiture development of novel therapeutic targets for the treatment of type 2 diabetes. 

Calpain Tissue specific calpains have been implicated in diabetes, cataracts, multiple sclerosis, and limb-girdle muscular dystrophy type 2A. More than 50 inhibitors of calpain have described which have a potential for therapeutic applications. 

Ca2+-sensing Receptor Calpains Protein Phosphates S100 Proteins... 

Calpains are proteolytic enzymes with cysteine in the catalytic site. In general, calpains are found as intracellular proteases. These proteases are associated with many physiological basic processes of the cell. 

In higher organisms, calpain superfamily contains 16 independent genes that modulate cellular function. Out of them, 14 are Ca2+-dependent cysteine proteases. The other two encode smaller regulatory proteins that... 

Calpains. Figure 1 Domain structures of calpain superfamily. Figure kindly provided by Dr. Hiroyuki Sorimachi, Laboratory of Biological Function, University of Tokyo, Japan. 

The calpain system has a number of different roles in cells, including remodeling of cytoskeleton attachments... 

Calpain inhibition may represent an important mechanism for future drug development. Control of calpain activity may limit the invasive properties of cells and thereby provides a possible mechanism to limit the invasiveness of tumors or inhibits the development of chronic inflammation. For the moment, pharmacological inhibitors of calpains are still not capable of differentiating among different calpain isoforms in cellular systems or in vivo. The importance of calpains in diseases will continue to stimulate the development of new and better inhibitors. 

More than 50 endogenous and exogenous inhibitors of the calpains have been described as either transition-state reversible or irreversible inhibitors. The first transition-state inhibitors were the peptide aldehydes (e.g., leupeptin). Using this compound, new ones were synthesized that exhibited improved membrane permeability and calpain specificity (e.g., calpeptin). Other groups of inhibitors have since been discovered a-dicarbonyls (originally developed as serine protease inhibitors), nonpeptide quinolinecarboxamides,... 

Calpains. Table 1 Examples of pathological conditions that have been associated to the calpains (Adapted from Goll et al.)... 

LGMD2A Caused by mutations in the calpain-3 gene and probable loss of calpain-3 proteolytic activity33... 

DMD and BMD DMD and BMD are caused by the absence or deficiency of dystrophin a membrane-associated protein, resulting in increased Ca2+ concentration in muscle, loss of Ca2+ homeostasis, and inappropriate calpain activity36... 

Alzheimer s disease Amount of m-calpain in the cytosolic but not the membranous fractions and in the neurofibrillary tangles of brain from Alzheimer s patients is increased37,38... 

Cataract formation Ca2+ influx activates m-calpain, the predominant calpain in lens, cleaving a- and 3- but not y-crystallins. The cry stall in fragments aggregate to form cataracts39... 

Myocardial infarcts Ca2+ homeostasis is lost in ischemic areas, triggering inappropriate calpain activity. Desmin and a-spectrin are degraded in ischemic hearts by synthetic calpain inhibitors. Protein and mRNA levels of m and (./-calpain increase after myocardial infarction40-43... 

Multiple sclerosis The 150-kDa calpain specific degradation product of a-spectrin increases 50% in human MS plaques.44 Degradation of the 68-kDa neurofilament protein is inhibited by a synthetic calpain inhibitor45... 

Obsessive-compulsive disorders Erythrocytes from patients with obsessive-compulsive disorder have significantly higher calpain activities than normal controls which could not be attributed to differences in memory function46... 

Neuronal ischemia Calpastatin is degraded by calpain to a membrane-bound 50-kDa polypeptide in ischemic... 

Perrin BJ, Huttenlocher A (2002) Molecules in focus calpain. Int J Biochem Cell Biol 34 722-725... 

Liu X, Van Vleet T, Schnellmann RG (2004) The role of calpain in oncotic cell death. Annu Rev Pharmacol Toxicol 44 349-370... 

Franco SJ, Huttenlocher A (2005) Regulating cell migration calpains make the cut. J Cell Sci 118 3829-3838... 

Zatz M, Starling A (2005) Calpains and diseases. N Engl JMed 352 2413-2423... 

CA C2 C02.001 Calpain-1 Drug target for stroke and neural injuries... 

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