Calpain - Discovery

Discovery

The history of calpain originates in 1964, when calcium-dependent proteolytic activities caused by a “calcium-activated neutral protease” (CANP) were detected in brain, lens of the eye and other tissues. In the late 1960s the enzymes were isolated and characterised independently in both rat brain and skeletal muscle. These activities were caused by an intracellular cysteine protease not associated with the lysosome and having an optimum activity at neutral pH, which clearly distinguished it from the cathepsin family of proteases. The calcium-dependent activity, intracellular localization, along with the limited, specific proteolysis on its substrates, highlighted calpain’s role as a regulatory, rather than a digestive protease. When the sequence of this enzyme became known, it was given the name “calpain”, to recognize it as a hybrid of two well-known proteins at the time, the calcium-regulated signalling protein, calmodulin, and the cysteine protease of papaya, papain. Shortly thereafter, the activity was found to be attributable to two main isoforms, dubbed μ("mu")-calpain and m-calpain (a.k.a. calpain I and II), that differed primarily in their calcium requirements in vitro. Their names reflect the fact that they are activated by micro- and nearly millimolar concentrations of Ca2+ within the cell, respectively.

To date, these two isoforms remain the best characterised members of the calpain family. Structurally, these two heterodimeric isoforms share an identical small (28k) subunit (CAPNS1 (formerly CAPN4)), but have distinct large (80k) subunits, known as calpain 1 and calpain 2 (each encoded by the CAPN1 and CAPN2 genes, respectively).