In autoimmune demyelinating diseases such as multiple sclerosis and EAE, the corresponding animal model, degradation of myelin proteins in CNS lesions suggested a role for calpain since all major myelin proteins are substrates of this enzyme. Calpain is a cytosolic cysteine endopeptidase (EC 22.214.171.124) that retains characteristics of the thiol proteinase, papain and calcium binding protein, calmodulin. The proteinase has been localized in every mammalian cell type studied, and calpain homologues have been identified in lower order organisms including nematodes, insects, yeast, and fungi96. The calpain family consists of at least six homologous members divided into two classes according to tissue distribution, i.e., ubiquitous or tissue specific. Recently discovered tissue specific calpains, such as p94 and nCL-2 (localized in muscle), exist as monomers or oligomers of the 80 kD catalytic subunit. Ubiquitous calpain is distributed in every cell, most often as a heterodimeric complex composed of 80 kD catalytic and 30 kD
regulatory subunits. Both ubiquitous calpain isoforms, millicalpain (mcalpain) and microcalpain (^calpain), share similar biochemical and catalytic properties with the exception of calcium concentrations required for activation. Approximately 1 -20^M and 250-750^M calcium levels are required for half-maximal activity of ^calpain and mcalpain, respectively, because calcium binding domains of the two isoforms differ in affinity for calcium97 98. Prior to activation, proenzyme calpain is normally associated with the endogenous inhibitor calpastatin. This association also requires calcium levels similar to the calcium activation requirement for each isoform. After calpain activation, calpastatin is also degraded by the active enzyme98,99.
Calpain has been described as a biomodulator because it degrades substrates in a limited fashion, resulting in alteration rather than destruction of the 'substrate. Calpain degrades a wide array of substrates including cytoskeletal and myofibrillar proteins, histones, enzymes, myelin proteins (myelin basic protein, MBP) and receptor protein13 100-104. Since calpain activation often occurs along the cell membrane, many membrane or membrane-associated proteins (actin-binding proteins such as fodrin, talin, filamin, a-actinin, and microtubule-associated proteins; growth factor receptors such as EGF receptors; adhesion molecules such as integrin, cadherin, N-CAM; and ion transporters such as Ca2+-ATPase) are calpain substrates105.
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