Calpain: Structure, biology and clinical significance

Calpains are class of proteins which belongs to the calcium dependent, non-lysosomal cysteine proteases. There are three major types of calpains expressed in muscle namely, μ-calpain, m-calpain and calpain 3, which shows proteolytic activities. Skeletal muscle fibres that possess all the three calpains also contain Ca²⁺-dependent proteases. The functional role of calpains was found to be associated with apoptosis and myogenesis. However, calpain 3 is likely to be involved in sarcomeric remodeling. A defect in the expression of calpain 3 results in limb-girdle muscular dystrophy type 2A. Calpain 3 is bound in skeletal muscle fibres at the N2A line of the large elastic protein, titin. A substantial proportion of calpain 3, but not ubiquitous calpains, is activated 24h after a single bout of eccentric exercise. In vitro studies indicated that calpain 3 can be activated to 2-4 folds higher than normal resting cytoplasmic [Ca²⁺] if exposed for a prolonged period of time and this suggests sustained increase in intracellular [Ca²⁺]. Characterization of calpain system in developing muscle is needed to indicate which calpastatin isoforms are present and whether both μ- and m-calpain exist in differentiating myoblasts. It has been demonstrated that the activation of ubiquitous calpains and calpain 3 in skeletal muscle is very well regulated in the presence of huge and rapid changes in intracellular [Ca²⁺]. Diabetes mellitus is recognized as a clinical syndrome that is characterized by hyperglycemia due to deficiency of insulin. Non-insulin dependent diabetes mellitus (NIDDM/Type-II), is multifactorial and exact biochemical and genetic defects have not been elucidated completely. The calpains seems to play a role in NIDDM and positional cloning experiments revealed NIDDM susceptibility to calpain 10 (CAPN 10). The increased calpain activity and leukocyte trafficking were noticed in the microcirculation of ZDF (Zuker diabetic fatty) rats. The exercise and low body weight play significant roles on the reducing the calpain expressions or elevating the calpains degradation in the skeletal muscle of NIDDM rats. Numerous investigations reported that non-coding polymorphisms in CAPN10 proteins may involved in the NIDDM. The calpain and its mRNA presence have been reported in tissues from many mammalian species while CAPN10 and other calpains seems to be linked with glucose metabolism, insulin secretion and action pathways.