Calpain is a thiol proteinase that is functionally active as a heterodimer composed of a small regulatory subunit and one of at least two large catalytic subunits (calpain 1 or calpain 2). In vitro, calpain 1 (mu-calpain) requires micromolar levels of calcium, while calpain 2 (M-calpain) requires millimolar levels of calcium for activation (1). Calpastatin negatively regulates autoproteolytic cleavage of calpain 1 between Gly27 and Leu28 in a calcium dependent manner (2). In particular, calpastatin binds and inhibits calpain when calcium levels are high and is released when calcium levels go down. Calpastatin contains five domains, a unique N-terminal domain L with no inhibitory effects and four homologous domains (CAST 1-4) that can inhibit heterodimeric calpain 1 and 2 (3).