Calpains in the Human Lens: Relations to Membranes and Possible Role in Cataract Formation

Abstract

Calpains are Ca-activated neutral proteases present in all cells together with an endogenous inhibitor, calpastatin. Proposed substrates are; cytoskeletal proteins like microtubules and actin, protein kinases such as PKC and membrane-bound enzymes like Ca-ATPase and the Ca-channel. In lenses from different species calpains have been detected in decreasing amounts from the epithelium to the cortex to the nucleus. Several substrates for calpain in the lens have been demonstrated: crystallins, vimentin, actin, beaded filaments and MP26 among others. Both studies on animal models and capsulor-hexis indicate that calpains are mainly involved in cortical cataract.

Defining a Link between Gap Junction Communication, Proteolysis, and Cataract Formation

“…Activation of calpains during the process of cataractogenesis has been extensively studied both in humans and in various mouse models (25)(26)(27). Three different calpains have been shown to be expressed in the lens, including m-calpain and the recently discovered lens-specific calpains, Lp82 and Lp85 (17, …”

Cataract Formation by a Semiquinone Metabolite of Acetaminophen in Mice: Possible Involvement of Ca2+and Calpain Activation

“…It awaits further studies to determine whether nuclear sequestration of Ca 2 precedes lens opacity development. In the lens, activation of calpain, a non-lysosomal Ca 2 -dependent cystein protease, appears to be involved in cataractogenesis in various cataract models (Andersson, Sjostrand and Karlsson, 1996;Matsushima et al, 1997;Kilic and Trevithick, 1998;Schey et al, 1999). Three types of calpain have been characterized: calpain I or m (Km for Ca 2 in mM), calpain II or m (Km for Ca 2 in mM), and calpain n (tissue speci®c) (Chan and Mattson, 1999).…”

“…Physiological substrates identi®ed for calpain include cytoskeletal proteins and adhesion molecules involved in structural changes of neural cells (Chan and Mattson, 1999) and muscle cells (Thyberg and Blomgren, 1999). Several proteins were reported to be substrates for calpain in the lens; crystallins and cytoskeletal proteins such as vimentin, actin, beaded ®laments, Mp26, and spectrin/fodrin (Ireland and Maisel, 1984;Truscott et al, 1989;Andersson et al, 1996;Matsushima et al, 1997;Kilic and Trevithick, 1998;Nakamura et al, 2000). Evidence in this work indicates that the breakdown of only a small fraction of lens vimentin (probably vimentin associated with surface epithelial cells) occurs in NAPQI-induced mouse cataract.…”

Anthracyclines Induce Calpain-dependent Titin Proteolysis and Necrosis in Cardiomyocytes

“…Although the exact physiological role of calpains in the myocardium is not known, the ability of calpains to cleave cytoskeletal and myofilament proteins desmin, fodrin, filamin, C-protein, tropomyosin, troponin T, troponin I, nebulin, gelsolin, and vinculin in a variety of cell types, in vitro, suggest a regulatory role for calpains in remodeling of the myofibril (15)(16)(17). Calpain activity is increased in a wide variety of pathological conditions associated with calcium overload including Alzheimer's disease (18,19), cataracts (20), oxidative stress (21), and ischemia reperfusion injury (22). In post-ischemic myocardium, the proteolytic activity of calpain may be linked to degradation of sarcomeric proteins troponin I and desmin (17,23).…”