Calpain Interactions with the Protein Phosphatase Calcineurin in Neurodegeneration

Dysregulation of intracellular Ca²⁺ is a major cause of neurologic dysfunction and likely plays an important role in the pathophysiology of numerous acute and chronic neurodegenerative conditions. The Ca²⁺-dependent protease, calpain, and the Ca²⁺/calmodulin (Ca²⁺/CaM)-dependent protein phosphatase, calcineurin, are primary effectors of multiple deleterious functions arising from altered Ca²⁺ handling. Increasing evidence suggests that the calpain-dependent, irreversible conversion of calcineurin to a constitutively active phosphatase occurs in intact cellular systems as a result of injury and disease. In this chapter, a brief overview of calpain and calcineurin functions in nervous tissue is given, followed by a more in-depth discussion of calpain/calcineurin interactions in vitro and in vivo. Particular emphasis is placed on recent studies that have identified calpain proteolysis of calcineurin as a key step in neurodegeneration associated with acute neurologic insults as well as chronic terminal diseases, like Alzheimer’s.