Regulation Of Calpain Activity The Calcium Requirement Problem
The calcium concentrations required for the activity of and m-calpains are much higher than the 50-300 nM found in the cytosol of living cells. Efforts have thus been made to identify possible mechanisms to reduce the calcium requirement of the calpains, focusing on factors that might act as "activators". Extensive work on phospholipids has shown (Coolican and Hathaway, 1984) that phosphoinositides lower the Ca2+-requirement of either m- or ^-calpain by three- to six-fold (Saido et al., 1992). Very high molar ratios of the phospho-lipids were required, making it unlikely that this mechanism would function under physiological conditions. It has been suggested that the calpains would interact with phospholipids at the plasma membrane, and that the interaction might lower the Ca2+requirement of the protease. This is an interesting suggestion; however, calpains bind to proteins and not to phospholipids in the plasma membrane (Inomata et al., 1990). Isovelerylcarnitine has been claimed to reduce the Ca2+-requirement for the activity of m-calpain to less than 10^M and to increase the specific activity of the protease (Pontremoli et al., 1990). A heat stable polypeptide (40-50kDa) isolated from human neutrophils (Pontremoli et al., 1988) and rat skeletal muscle (Pontremoli et al., 1990), has also been shown to reduce the Ca2+ concentration required for proteolytic activity of m-calpain. A dimeric protein of 30kDa, later identified as an acyl-CoA binding protein, has also been claimed to reduce the Ca2+-requirement for m-calpain from a variety of sources (Melloni et al., 1998). Other activators have also been described, including nuclear DNA (Mellgren et al., 1993) and calpastatin subdomain A and C (see below) (Tompa et al., 2002). In summary, the mechanisms to reduce the calcium requirement of calpains are still obscure.
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