Hypothetical scheme for calpain activation in the stomach pit cells.

(Upper) In the stomach pit cells, in addition to the conventional μ- and m-calpains, G-calpain is predominantly expressed. To be activated by Ca2+, G-calpain requires both catalytic subunits, which intramolecularly and intermolecularly autolyze, probably dissociating from each other. The proteolytic activity of at least calpain 8 is essential for the physiological function of G-calpain, that is, stress-induced gastric mucosal protection. We previously found that calpain 8, when transiently expressed without calpain 9 in cultured cells or in E. coli, forms homo-oligomers [11]. Although the physiological significance of this homo-oligomerization is unclear, it may play a role in modulating the activation of G-calpain under certain conditions. (Lower) In contrast, conventional μ- and m-calpains require a regulatory subunit, CAPNS1, but not other catalytic subunits, to be Ca2+-dependently activated to proteolyze their substrates, although it remains controversial whether or not their activation involves the dissociation of subunits, as illustrated here [40]–[42]. Since the stomach is under frequent stress, an extra calpain system in addition to the conventional one may have been required to respond swiftly to stresses.