Calpain proteinases are defined currently as papain like neutral proteases that are calcium activated. Calpains 1 and 2 are composed of a large subunit, which is proteolytically active, and a small subunit (also called calpain 4), or enhancer protein, that is not proteolytically active. The other calpain proteins identified to date are not known to require a small subunit, although there is evidence that the calpain small subunit #2 may act as a chaperonin in the folding of calpains, and then disassociate. Domains in the large subunit include the amino terminal domain I, the proteinase domain II, domain III, and the EF hand domain IV (Domain T in calpains 5 & 6). Calpain 8, also known as NCL 2 (novel calpain 2), was originally characterized in rodents as a stomach specific protein, but the human sequence was isolated from leukocytes. Most similar to calpain 2 (60 % identical to rat or human sequences), murine calpain 8 is also known as a truncated form (Calpain NCL-2), lacking the calcium binding domain, and most of domain III. Homology between human calpain 8 and human calpain 9 (the human stomach specific calpain) is much lower; calpain 9 is more similar to calpain 3. Homology between rat, mouse and human calpain 8 is high. The large subunit of calpain 8 zymogen runs at approximately 80 Kd, and the amino terminal truncation at activation yields an approximately 60 kD form. Cleavage of the carboxyterminal region generates smaller forms of Calpain 8, but it is not clear if these forms are proteolytically active.