Disease relevance of Capn1

• Using the inactive C105S-80k/21k form of calpain to eliminate autolysis, we have studied its disassociation and aggregation in the presence of Ca(2+) and the inhibition of its aggregation by means of crystallization, light scattering, and sedimentation [1].
• In conclusion, MDL28170 abated calpain I activation, inhibited apoptosis and neuron loss, quenched microglia and astrocyte activation, and significantly improved neurologic deficit one week after spinal cord hemisection [2].
• These data indicate that calpain inhibitors could represent a viable strategy for preserving the cytoskeletal structure of injured neurons after experimental traumatic brain injury in vivo [3].
• Calpain activity and expression are increased in splenic inflammatory cells associated with experimental allergic encephalomyelitis [4].
• Since calcium-activated neutral proteinase (calpain) activity and expression are significantly increased in activated glial/inflammatory cells in the central nervous system of animals with autoimmune demyelinating diseases, this enzyme may also play a role in peripheral organ systems in these diseases [4].

Psychiatry related information on Capn1

• beta-Amyloid((1-40))-induced apoptosis of cultured cortical neurones involves calpain-mediated cleavage of poly-ADP-ribose polymerase. beta-Amyloid protein is thought to contribute to the pathophysiology of Alzheimer's disease by inducing neuronal apoptosis [5].
• However, its potential in Huntington's disease (HD) models characterized by calpain-dependent degeneration and inflammation has not been investigated [6].
• In contrast, no change occurred in the levels of muscle mRNAs encoding cathepsin L, cathepsin D and calpain 1 on denervation or food deprivation [7].

High impact information on Capn1

• 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 [8].
• Here we show that activation of the protease core of mu calpain requires cooperative binding of two Ca(2+) atoms at two non-EF-hand sites revealed in the 2.1 A crystal structure [8].
• A Ca(2+) switch aligns the active site of calpain [8].
• Conservation of the Ca(2+) binding residues defines an ancestral general mechanism of activation for most calpain isoforms, including some that lack EF-hand domains [8].
• The putative protein revealed a potential calmodulin-binding site and six regions with amino acid compositions (PEST regions) common to proteins that are susceptible to calpain [9].

Chemical compound and disease context of Capn1

• Spectrin breakdown products mediated by calpain 1 activation were detectable in both hemispheres 24 h after traumatic brain injury and were substantially reduced in animals treated with calpain inhibitor 2 both ipsilaterally and contralaterally to the site of injury [3].
• PD 123319 did not affect calpain I or II up-regulation in the infarcted myocardium, but decreased interstitial fibrosis [10].
• Ramipril and valsartan decreased mRNA and protein up-regulation of calpain I and II, and reduced infarct size and interstitial fibrosis [10].
• We studied calpain expression in rat C6 glioma cells exposed to reactive hydroxyl radical (.OH) [formed via the Fenton reaction (Fe2++H2O2+H+-->Fe3++H2O+.OH)], interferon-gamma (IFN-gamma), and calcium ionophore (A23187) [11].
• Diverse stimuli induce calpain overexpression and apoptosis in C6 glioma cells [11].

Biological context of Capn1

• These results suggested that Lp82 might regulate other calpain activities and cause hydrolysis of substrates such as crystallins during lens cataract formation [12].
• Calpain is a heterodimeric Ca(2+)-dependent cysteine protease consisting of a large (80 kDa) catalytic subunit and a small (28 kDa) regulatory subunit [1].
• Exposure of the hydrophobic dimerization surface following subunit dissociation may be the main factor responsible for Ca(2+)-induced aggregation of calpain [1].
• Reverse transcription polymerase chain reaction demonstrated calpain inhibition significantly attenuated the ratio of proapoptotic Bax/anti-apoptotic Bcl-2 mRNA in the lesion and penumbra after SCI [2].
• Calpain, a calcium-dependent cytosolic cysteine protease, is implicated in a multitude of cellular functions but also plays a role in cell death [13].

Anatomical context of Capn1

• Force-[Ca2+] relations were compared before and 5 to 30 minutes after direct exposure of skinned trabeculae to calpain I (18 microgram/mL, 20 minutes at [Ca2+]=10.8 micromol/L), a Ca2+-activated protease that is present in myocardium [14].
• Nerve growth factor-induced decrease in the calpain activity of PC12 cells [15].
• Both the decrease in calpain activity and the growth of neurites are reversible upon the removal of nerve growth factor from the cultures [15].
• Double labeling of calpain I and phosphorylated tau (AT8) in the same cells of spinal cord lesion further implicated pathogenesis of SCI [2].
• Calpain expression varies among different rat and bovine central nervous system regions [16].

Associations of Capn1 with chemical compounds

• At low ionic strength, calpain aggregated rapidly in the presence of Ca(2+), but this was fully reversible by EDTA [1].
• Oxidized lipoproteins inhibit surfactant phosphatidylcholine synthesis via calpain-mediated cleavage of CTP:phosphocholine cytidylyltransferase [17].
• Agents other than nerve growth factor that cause neurite outgrowth, such as fibroblast growth factor and dibutyryl cyclic AMP, also cause a decrease in calpain activity [15].
• To explore a possible role for calpain in neuronal PCD under oxidative stress and Ca2+ influx, we examined the effects of H2O2 and A23187 on PC12 cells [18].
• We conclude that calpain overexpression due to.OH stress, IFN-gamma stimulation, or Ca2+ influx is involved in C6 cell death, which is attenuated by a calpain-specific inhibitor [11].

Physical interactions of Capn1

• 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 [19].
• More importantly, calpain activation resulted in the disruption of GRIP binding to the GluR2 subunit of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors [20].

Enzymatic interactions of Capn1

• In this study, we report that p35 can be cleaved to p25 both in vitro and in vivo by calpain [21].
• Calpain cleaves myosin-Va in vitro at methionine 1141 in the tail domain [22].
• Previously we reported that calpain cleaved Bid in the absence of detectable caspase activation (1) [23].
• Under the same conditions, calmodulin-dependent protein kinase II-alpha (CaMPK-IIalpha) and neuronal nitric oxide synthase (nNOS) are both proteolytically cleaved by calpain [24].
• Accumulation of non-erythroid alpha II-spectrin and calpain-cleaved alpha II-spectrin breakdown products in cerebrospinal fluid after traumatic brain injury in rats [25].

Regulatory relationships of Capn1

• Calpastatin-containing fractions from extracts of nerve growth factor-treated cells inhibit more calpain activity than do comparable fractions from control cells [15].
• In conclusion, proteolysis of calpastatin by caspase 3 may regulate calpain activity during I/R injury [26].
• The down-regulation of NMDAR current was blocked by bath application of selective calpain inhibitors [27].
• Our results showed that calpain can down-regulate the caspase-9/caspase-3 cell death pathway during neurodegeneration due to chronic mitochondrial defects in vivo and that this effect may involve, at least in part, direct cleavage of the caspase-3 p20 subunit [28].
• The data suggest that synaptobrevin, syntaxin, and SNAP-25 are subject to proteolytic modification by activated calpain in intact type II cells stimulated for secretion [29].

Other interactions of Capn1

• Calpastatin, a specific calpain inhibitor prevented the effects of calpain I on skinned trabeculae [14].
• Calpain-dependent proteolytic cleavage of the p35 cyclin-dependent kinase 5 activator to p25 [21].
• Twelve times more calpain 2 mRNA than calpain 1 was present in retinas [30].
• In contrast, in HT22 cells, only the activation of calpain and upregulation and translocation of AIF occurred [31].
• The effects of Ox-LDL on CCTalpha breakdown were attenuated in calpain-deficient cells [17].

Analytical, diagnostic and therapeutic context of Capn1

• Calpain levels, as detected with immunoblotting or immunohistochemistry, show no decrease [15].
• This cleavage was inhibited by a calpain inhibitor peptide derived from calpastatin and was ablated by separating the p35.CDK5 from calpain by centrifugation [21].
• Calpain activation and calpastatin expression in the pancreatic tissue were studied by Western blot analysis [13].
• 3-[2-[4-(3-Chloro-2-methylphenylmethyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole Dihydro-chloride 3.5 Hydrate (DY-9760e) Is Neuroprotective in Rat Microsphere Embolism: Role of the Cross-Talk between Calpain and Caspase-3 through Calpastatin [32].
• Immunoblotting was used to detect activation of calpain and proteolysis of substrates [30].

References