Disease relevance of Capn1

• Here, we identify two calpain cleavage sites in Htt and show that mutation of these sites renders the polyQ expanded Htt less susceptible to proteolysis and aggregation, resulting in decreased toxicity in an in vitro cell culture model [1].
• Calpain activation and secretion promote glomerular injury in experimental glomerulonephritis: evidence from calpastatin-transgenic mice [2].
• Wild-type mice that were subjected to anti-glomerular basement membrane nephritis exhibited elevated levels of calpain activity in kidney cortex at the heterologous phase of the disease [2].
• There also was a reduction in nephrin disappearance from the surface of podocytes, indicating that calpain activity would enhance proteinuria by affecting nephrin expression [2].
• Taken together, these results strongly suggest that epigenetic activation of calpain plays an important role in the invasion of human prostate cancer and that it can be targeted to reduce tumor progression [3].

Psychiatry related information on Capn1

• Caspase 3-cleaved N-terminal fragments of wild-type and mutant huntingtin are present in normal and Huntington's disease brains, associate with membranes, and undergo calpain-dependent proteolysis [4].
• Calpain inhibitors: a treatment for Alzheimer's disease [5].

High impact information on Capn1

• Furthermore, inhibition of cdk5 or calpain activity reduces cell death in A beta-treated cortical neurons [6].
• Specific inhibitors of calpain, a calcium-dependent cysteine protease, effectively inhibit the calcium-induced cleavage of p35 [6].
• We thus hypothesize an important function for calpain in sculpting the B cell repertoire [7].
• MEKK1 is required for activation of the cysteine protease calpain and cleavage of spectrin and talin, proteins linking focal adhesions to the cytoskeleton [8].
• Therefore, MEKK1 regulates calpain-mediated substratum release of migrating fibroblasts [8].

Chemical compound and disease context of Capn1

• Platelet factor XIII and calpain negatively regulate integrin alphaIIbbeta3 adhesive function and thrombus growth [9].
• There is limited evidence that inhibition of the activity of the cytosolic cysteine protease calpain reduces ischemia/reperfusion injury [10].
• Pseudomonas aeruginosa (PA103) decreased DPPC synthesis, in part, via calpain-mediated degradation of CCTalpha [11].
• Supporting a role of mu-calpain in producing cTnT-ND in myocardial ischemia reperfusion, calpain inhibitors decreased the level of cTnT-ND in Triton-extracted myofibrils. mu-Calpain treatment of the cardiac myofibril and troponin complex specifically reproduced cTnT-ND [12].
• Buthionine sulfoximine induced cataracts in mice contain insolubilized crystallins with calpain II cleavage sites [13].

Biological context of Capn1

• Previous studies have shown a correlative relationship between calcium-dependent protease (calpain) activity in dystrophic muscle and muscle necrosis, but have not tested whether calpain activation precedes cell death or is a consequence of it [14].
• Downregulation of phosphoinositide production by 1-butanol resulted in diminished PIP(2) in the plasma membrane and eliminated EGF-induced calpain activation [15].
• Disruption of the murine calpain small subunit gene, Capn4: calpain is essential for embryonic development but not for cell growth and division [16].
• Homozygous disruption of murine Capn4 eliminated both mu- and m-calpain activities, but this did not affect survival and proliferation of cultured embryonic stem cells or embryonic fibroblasts, or the early stages of organogenesis [16].
• Group B Streptococcus induces macrophage apoptosis by calpain activation [17].

Anatomical context of Capn1

• To assess the role of calpain in migration, we used fibroblasts obtained from Capn4(-/-) mouse embryos [18].
• The experiments in this study were undertaken to determine whether inhibition of calpain activity in skeletal muscle is associated with alterations in muscle metabolism [19].
• The results demonstrate unequivocally that calpain is a critical regulator of cell migration and of the organization of the actin cytoskeleton and focal adhesions [18].
• Calpain I induces cleavage and release of apoptosis-inducing factor from isolated mitochondria [20].
• Calpeptin and the mitochondrial permeability transition pore antagonist cyclosporin A also inhibited calcium-induced AIF release from mouse liver mitochondria, implicating the involvement of an endogenous mitochondrial calpain in release of AIF during permeability transition [20].

Associations of Capn1 with chemical compounds

• This PIP(2)-binding capacity resided in domain III of calpain, which presents a putative C2-like domain [15].
• Enzymatic inhibition of calpain by calpeptin precluded AIF release, demonstrating that proteolytic activity was required for release [20].
• Calpain Is Required for the Rapid, Calcium-dependent Repair of Wounded Plasma Membrane [21].
• Capn4(-/-) MEFs displayed resistance to puromycin, camptothecin, etoposide, hydrogen peroxide, ultraviolet light, and serum starvation, which was consistent with pro-apoptotic roles for calpain [22].
• Calpain, a calcium-activated cysteine protease, has been shown to participate in the development of the inflammatory process [2].

Physical interactions of Capn1

• In addition, I-benzyl-CH=C(SH)COOH (PD150606), a calpain inhibitor directed toward the calcium binding sites of calpain, also prevents apoptosis [23].
• Somatostatin increases glucocorticoid binding and signaling in macrophages by blocking the calpain-specific cleavage of Hsp 90 [24].
• In the presence of calcium ions, muCANP bound to the erythrocyte membranes as a heterodimer of 79- and 28-kDa subunits and was converted quickly on the membranes to an active form with a 76-kDa large subunit [25].

Enzymatic interactions of Capn1

• Both precursor and mature forms of recombinant AIF were cleaved near the amino terminus by calpain I in vitro [20].
• The structural requirements of PKC were then examined using a calpain-cleaved active fragment of nPKC delta [26].
• Most interestingly, n-3 PFA deficiency dramatically increased levels of protein fragments, corresponding to caspase/calpain-cleaved fodrin and gelsolin in Tg2576 mice [27].

Regulatory relationships of Capn1

• Because elevated intracellular calcium is one of the most ubiquitous features of neuronal cell death, this study tested the hypothesis that cleavage of AIF by the calcium-activated protease calpain mediates its release from mitochondria [20].
• With differential ligand-induced internalization and trafficking-restricted receptor variants, we find that calpain activity is triggered only by plasma membrane-restricted activated EGFR, not by internalized (although still active) EGFR [28].
• The association of calpain with the plasma membrane was verified by immunoblots of isolated sarcolemmal membrane from adult mdx and control muscle which showed calpain present predominantly in the cytosol along with some membrane association [29].
• Calpain inhibitors suppressed NF-kappaB activation via inhibition of the cleavage of inhibitor of NF-kappaB(IkappaBalpha)in RAW 264.7 cells [30].
• In addition, we showed that activation of cellular calpains by Ca2+ ionophore treatment reduces utrophin protein levels in muscle cells and that calpain inhibition prevents this Ca2+ -induced reduction in utrophin levels [31].

Other interactions of Capn1

• Taken together, these results define a novel mechanism of AIF release involving calpain processing and identify a potential molecular checkpoint for cytoprotective interventions [20].
• Epidermal growth factor receptor activation of calpain is required for fibroblast motility and occurs via an ERK/MAP kinase signaling pathway [32].
• In contrast, capn4(-/-) MEFs were more susceptible to staurosporine (STS) and tumor necrosis factor alpha-induced cell death, which provided evidence for anti-apoptotic signaling roles for calpain [22].
• Interestingly, calpain-1, -5, -7, and -10 localize to the cytoplasm and the nucleus, whereas the activated forms of calpain-7 and -10 are found only in the nucleus [1].
• Recent studies have implicated both extracellular signal-regulated kinase/mitogen-activated protein (ERK/MAP) kinase and calpain (EC 3.4.22.17) in these processes, but it is uncertain whether these are two distinct pathways acting on different modes of motility [32].
• Together, our results demonstrate that PTP1B is a physiological target of calpain-1 and suggest that a similar mechanism may regulate calpain-1-mediated tyrosine dephosphorylation in other cells [33].

Analytical, diagnostic and therapeutic context of Capn1

• Caspase-3 activity increased, but to a lesser extent than calpain activation (measured by fluorimetry and calpain-cleaved alpha-spectrin) [34].
• The complete deficiency of mu-calpain causes significant reduction in platelet aggregation and clot retraction but surprisingly the mutant mice display normal bleeding times [35].
• By western blot and immunofluorescence, ezrin, a substrate for calpain, was also found to decrease in the pulmonary epithelium of foxj1(-/-) mice [36].
• Western blot analysis revealed an increase in the levels of mu-calpain (calpain-1) in the cytosolic fraction of infected cerebral cortex and cerebellum although a decrease in the level of m-calpain was observed in the cytosolic fraction of infected cerebellum and cerebral cortex [37].
• The cellular distributions of mRNA for calpain I or calpastatin, measured by in situ hybridization, are relatively uniform throughout the brain [38].

References