Analyzing the Behavior of Neuronal Pathways in Alzheimer's Disease Using Petri Net Modeling Approach

The calpain system originally comprised three molecules: two Ca2+-dependent proteases, mu-calpain and m-calpain, and a third polypeptide, calpastatin, whose only known function is to inhibit the two calpains. Both mu- and m-calpain are heterodimers containing an identical 28-kDa subunit and an 80-kDa subunit that shares 55-65% sequence homology between the two proteases. The crystallographic structure of m-calpain reveals six "domains" in the 80-kDa subunit: 1). a 19-amino acid NH2-terminal sequence; 2). and 3). two domains that constitute the active site, IIa and IIb; 4). domain III; 5). an 18-amino acid extended sequence linking domain III to domain IV; and 6). domain IV, which resembles the penta EF-hand family of polypeptides. The single calpastatin gene can produce eight or more calpastatin polypeptides ranging from 17 to 85 kDa by use of different promoters and alternative splicing events. The physiological significance of these different calpastatins is unclear, although all bind to three different places on the calpain molecule; binding to at least two of the sites is Ca2+ dependent. Since 1989, cDNA cloning has identified 12 additional mRNAs in mammals that encode polypeptides homologous to domains IIa and IIb of the 80-kDa subunit of mu- and m-calpain, and calpain-like mRNAs have been identified in other organisms. The molecules encoded by these mRNAs have not been isolated, so little is known about their properties. How calpain activity is regulated in cells is still unclear, but the calpains ostensibly participate in a variety of cellular processes including remodeling of cytoskeletal/membrane attachments, different signal transduction pathways, and apoptosis. Deregulated calpain activity following loss of Ca2+ homeostasis results in tissue damage in response to events such as myocardial infarcts, stroke, and brain trauma.

Cellular Ca(2+) homeostasis is maintained through the integrated and coordinated function of Ca(2+) transport molecules, Ca(2+) buffers and sensors. These molecules are associated with the plasma membrane and different cellular compartments, such as the cytoplasm, nucleus, mitochondria, and cellular reticular network, including the endoplasmic reticulum (ER) to control free and bound Ca(2+) levels in all parts of the cell. Loss of nutrients/energy leads to the loss of cellular homeostasis and disruption of Ca(2+) signaling in both the reticular network and cytoplasmic compartments. As an integral part of cellular physiology and pathology, this leads to activation of ER stress coping responses, such as the unfolded protein response (UPR), and mobilization of pathways to regain ER homeostasis.