The intriguing Ca2+ requirement of calpain activation.

Mammalian ubiquitous micro- and m-calpains, as well as their Drosophila homologs, Calpain A and Calpain B, are Ca(2+)-activated cytoplasmic proteases that act by limited proteolysis of target proteins. Calpains are thought to be part of many cellular signaling pathways. These enzymes, however, require such high Ca(2+) concentration for half-maximal activation in vitro, [Ca(2+)](0.5), that hardly ever occurs in intact cells. This major dilemma has pervaded the literature on calpains for decades. In this paper several considerations are put forward that challenge the orthodox view and envisage mechanisms that may govern calpain action in vivo. The "unphysiologically" high Ca(2+) demand for activation may turn out to be an evolutionarily adjusted safety device.