How is alteration in Ca2+ homeostasis controlled in brain? A role for calpastatin

A number of reports have indicated a role of calpain in the degradation of brain structures in neurodegenerative diseases. In these studies, the endogenous regulatory protein calpastatin appears to be ineffective and synthetic inhibitors or over‐expression of calpastatin are required to reduce proteolysis by calpain. To define the “in vivo” efficiency of calpastatin, we have investigated the effect of a high salt diet (HSD), promoting a mild increase in [Ca 2+ ] i , in brain of normal NMS and of hypertensive HMS rats, in which [Ca 2+ ] i is constitutively altered. In brain of both animals the prolonged increase in [Ca 2+ ] i produced, as expected, calpain activation. At the plasma membranes, Ca 2+ ‐ATPase is selectively degraded, whereas cytosolic calpastatin appears to be a preferential target, undergoing slow inactivation and conversion to still active low Mr fragments. This HSD‐induced proteolytic activity , more pronounced in brain of HMS rats, is not followed by irreversible cell damages being efficiently controlled by a combined process leading to the restoration of normal conditions. Altogether, our results demonstrate that “in vivo” increased expression of Ca 2+ ‐ATPase, temporarily followed by an increased calpastatin synthesis, results in a more efficiently controlled calpain activity and thereby reducing the extent of protein degradation. This work was supported by grants from MIUR.