Disease relevance of Cast

• A calpain inhibitor attenuates cortical cytoskeletal protein loss after experimental traumatic brain injury in the rat [1].
• After treatment of rats either without or with calpain inhibitor Z-Val-Phe methyl ester (ZVP; 60 mg/kg i.p.), pancreatitis was induced by cerulein injections (10 microg/kg i.p.; 5 times at hourly intervals) [2].
• In this study, the activity and expression of calpain and the endogenous inhibitor, calpastatin, were evaluated at transcriptional and translational levels in spleens of Lewis rats with acute experimental allergic encephalomyelitis (EAE) prior to the onset of clinical symptoms [3].
• Sepsis resulted in increased muscle calpain activity caused by reduced calpastatin activity [4].
• This conclusion was based on data showing proteolysis of a calpain substrate alpha-spectrin, autolysis of activated calpain, and reduction of cell damage by calpain inhibitor SJA6017 [5].

High impact information on Cast

• The protease region is not affected by the endogenous inhibitor, calpastatin, and may contribute to calpain-mediated pathologies when the core is released by autoproteolysis [6].
• In contrast, animals pretreated with the calpain inhibitor showed minimal evidence of apoptosis [7].
• METHODS: Hepatocytes from Wistar rats were injured with tertbutyl hydroperoxide in the presence or absence of ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) or a specific calpain inhibitor, calpeptin (Z-Leu-nLeu-H) [8].
• Calpain inhibitor AK295 attenuates motor and cognitive deficits following experimental brain injury in the rat [9].
• Upregulation of calpastatin in regenerating and developing rat liver: role in resistance against hepatotoxicity [10].

Chemical compound and disease context of Cast

• Here we show that in both of these examples of glutamate receptor-mediated toxicity, activation of a calpainlike proteolytic activity occurred, which was blocked by the calpain inhibitor MDL-28170 [11].
• The calpain inhibitor MDL 28170 prevents inflammation-induced neurofilament light chain breakdown in the spinal cord and reduces thermal hyperalgesia [12].
• The effect of the newly developed, nonpeptide, calpain inhibitor, PD 150606, on hypoxia and ionomycin-induced increases in calpain activity in rat proximal tubules (PT) was determined [13].
• To determine the possibility of a 'calpain burst' impacting cardiac calpastatin inhibitory activity, rat hearts were subjected (Langendorff) to either 45 or 60 min of ischemia followed by 30 min of reperfusion with and without pre-administration (s.c.) of a cysteine protease inhibitor (E-64c) [14].
• The results supported the idea that application of calpain inhibitor is beneficial in prevention of rodent selenite cataracts [15].

Biological context of Cast

• Higher calpastatin levels correlate with resistance to calpain-mediated proteolysis and neuronal apoptosis in juvenile rats after spinal cord injury [16].
• On day 1, 3, 7 and 14 after MI, gene expression and protein levels of calpain I, II and calpastatin were determined in left ventricular free wall (LVFW) and interventricular septum (IS) [17].
• Other differences, due to exon skipping, produce calpastatin forms with different susceptibility to posttranslational modifications [18].
• Pretreatment of C6 cells with calpeptin (a cell-permeable calpain inhibitor) blocked calpain overexpression, MAG degradation, and DNA fragmentation [19].
• Calpain inhibitor SJA6017 may have potential for testing as a therapeutic agent against retinal pathologies such those caused by glaucoma, although future studies such as testing in in vivo animal models are required [5].

Anatomical context of Cast

• These studies suggest that nerve growth factor causes a decrease in the activity of calpain in morphologically differentiating PC12 cells by causing an increase in the activity of calpastatin [20].
• Calpain and calpastatin translational expression levels were greatest in the spinal cord [21].
• Translational expression of bovine calpain was greatest in the brain stem, while that of calpastatin was highest in the cerebral cortex [21].
• Overexpression of calpastatin inhibits L8 myoblast fusion [22].
• Sepsis stimulates calpain activity in skeletal muscle by decreasing calpastatin activity but does not activate caspase-3 [4].

Associations of Cast with chemical compounds

• Western blotting analysis showed that FPL 64176 and (S)-(-)-Bay K8644 increased the cleavage of PKC to generate protein kinase M (PKM) and the specific calpain inhibitor MDL28170 blocked this increase [23].
• Sepsis-induced muscle proteolysis was blocked by the calpain inhibitor calpeptin but was not influenced by the caspase-3 inhibitor Ac-DEVD-CHO [4].
• Here, we developed a membrane-permeable specific calpain inhibitor by fusing calpastatin peptide (CS) and 11 poly-arginine peptides (11R) [24].
• Calpastatin decreases the activity of mCANP and, in the presence of polyunsaturated fatty acids such as docosahexaenoic acid, the inhibition is not increased [25].
• We investigated the role of gonadal steroids in the sex differences in RW disease severity in male (M) and female (F), castrated (Cast), and ovariectomized (OVX) rats and after dihydrotestosterone (DHT) and 17beta-estradiol (E2) treatment [26].

Physical interactions of Cast

• Although calpastatin by complexing initially to calpain can prevent the association of this protease with subcellular organelles, it cannot dissociate calpains already bound to these subcellular fractions [27].

Enzymatic interactions of Cast

• Lp82 also hydrolyzed calpastatin [28].

Regulatory relationships of Cast

• Calpastatin-containing fractions from extracts of nerve growth factor-treated cells inhibit more calpain activity than do comparable fractions from control cells [20].
• Calpastatin inhibited calpain 2 activity, but not Lp82 [28].
• In addition, calpastatin appears to modulate myogenic gene expression, as indicated by the lack of myogenin (a transcription factor expressed in differentiating myoblasts) in myoblasts overexpressing calpastatin [22].
• These data suggest that Lp82-induced proteolysis in rodent lenses may occur even in the presence of calpastatin [29].
• A corresponding production of stable, carboxy-terminal gephyrin fragments of 48-50 kDa occurred within 1 min of proteolytic activation and was blocked by the selective calpain inhibitor CX295 [30].

Other interactions of Cast

• Calpastatin, a specific calpain inhibitor prevented the effects of calpain I on skinned trabeculae [31].
• The mRNA levels of calpastatin (endogenous calpain inhibitor) and beta-actin (house-keeping) genes were not changed [32].
• In addition, in vivo caspase inhibition reverses the decrease in calpastatin activity [33].
• On the protein level, calpain 9 but not calpastatin was regulated in the hypertensive target organs heart and kidney [34].
• The pre-ischemic perfusion and post-ischemic reperfusion of hearts with a cell-permeable calpain inhibitor (N-Ac-Leu-Leu-methioninal) suppressed the increase in calpain expression and reversed the localization of NMT from nucleus to cytoplasm [35].

Analytical, diagnostic and therapeutic context of Cast

• This cleavage was inhibited by a calpain inhibitor peptide derived from calpastatin and was ablated by separating the p35.CDK5 from calpain by centrifugation [36].
• The transcriptional expression of millicalpain, microcalpain, and calpastatin as examined by RT-PCR was not significantly increased in EAE [37].
• Protein levels of mu- and m-calpain and calpastatin were determined by Western blotting, and calpastatin mRNA was measured by real-time PCR [4].
• In the present study, we used immunoprecipitation to investigate the molecular association between calpain and calpastatin in dividing myoblasts and in the initial stages of myoblast differentiation [38].
• CAI (0.5 mg/kg) was administered 10 min before the 30-min ischemia (CAI-A group) and 10 min before the 6-h reperfusion period (CAI-B group) [39].

References