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.

The Calpain System

Mammalian skeletal muscle shows an enormous variability in its functional features such as rate of force production, resistance to fatigue, and energy metabolism, with a wide spectrum from slow aer...

Calcium Ion in Skeletal Muscle: Its Crucial Role for Muscle Function, Plasticity, and Disease

Cachexia — the massive (up to 80%) loss of both adipose tissue and skeletal muscle mass — is a significant factor in the poor performance status and high mortality rate of cancer patients. Although this metabolic defect has been known since cancer was first studied, it is only recently that major advances have been made in the identification of catabolic factors that act to destroy host tissues during the cachectic process. Although anorexia is frequently present, depression of food intake alone seems not to be responsible for the wasting of body tissues, as nutritional supplementation or pharmacological manipulation of appetite is unable to reverse the catabolic process — particularly with respect to skeletal muscle. However, recent clinical studies in cancer patients have shown that nutritional supplementation can be effective when combined with agents that attenuate the action of tumour factors and modifiers of the central effects on appetite might also show promise.

Cachexia in cancer patients

Muscle Protein Breakdown and the Critical Role of the Ubiquitin-Proteasome Pathway in Normal and Disease States

Biochemistry of postmortem muscle - lessons on mechanisms of meat tenderization.

Role of the calpain system in muscle growth

The structure of human platelets differs from that of bovine platelets in that human platelets have a surface-connected canalicular system that bovine platelets lack. Platelets are one of the richest known sources of the calpains, and the calpains have been implicated in many of the specific cleavages of cytoskeletal and surface-receptor proteins that occur during platelet activation and aggregation. Several studies have reported that human platelets are rich in mu-calpain and contain less m-calpain, whereas bovine platelets contain principally m-calpain and almost no mu-calpain. The immunolocalization studies reported here show that calpastatin is distributed throughout the cytosol of both human and bovine platelets and that calpain is located throughout the interior of human platelets. Calpain in bovine platelets is located primarily in alpha-granules, however. Because bovine platelets contain predominantly m-calpain and because alpha-granules are translocated to the platelet surface during activation, bovine m-calpain may be responsible for the specific cleavages of platelet surface proteins such as glycoprotein Ib that occur during platelet activation and at extracellular Ca2+ concentrations high enough to activate m-calpain.

J.A. Christiansen

Papers

Role of the calpain system in muscle growth

Immunolocalization of the calpains and calpastatin in human and bovine platelets.