Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overactivation of calcium-activated neutral protease (calpain) has been implicated in the pathophysiology of several degenerative conditions, including stroke, myocardial ischemia, neuromuscular degeneration, and cataract formation. Alpha-mercaptoacrylate derivatives (exemplified by PD150606), with potent and selective inhibitory actions against calpain, have been identified. PD150606 exhibits the following characteristics: (i) Ki values for mu- and m-calpains of 0.21 microM and 0.37 microM, respectively, (ii) high specificity for calpains relative to other proteases, (iii) uncompetitive inhibition with respect to substrate, and (iv) it does not shield calpain against inactivation by the active-site inhibitor trans-(epoxysuccinyl)-L-leucyl-amido-3-methylbutane, suggesting a nonactive site action for PD150606. The recombinant calcium-binding domain from each of the large or small subunits of mu-calpain was found to interact with PD150606. In low micromolar range, PD15O6O6 inhibited calpain activity in two intact cell systems. The neuroprotective effects of this class of compound were also demonstrated by the ability of PD150606 to attenuate hypoxic/hypoglycemic injury to cerebrocortical neurons in culture and excitotoxic injury to Purkinje cells in cerebellar slices.
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PMID:An alpha-mercaptoacrylic acid derivative is a selective nonpeptide cell-permeable calpain inhibitor and is neuroprotective. 869 79

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.
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PMID:The calpain system. 1284 8

Hyperhomocysteinemia (HHcy) is associated with atherosclerosis, stroke, and dementia. Hcy causes extracellular matrix remodeling by the activation of matrix metalloproteinase-9 (MMP-9), in part, by inducing redox signaling and modulating the intracellular calcium dynamics. Calpains are the calcium-dependent cysteine proteases that are implicated in mitochondrial damage via oxidative burst. Mitochondrial abnormalities have been identified in HHcy. The mechanism of Hcy-induced extracellular matrix remodeling by MMP-9 activation via mitochondrial pathway is largely unknown. We report a novel role of calpains in mitochondrial-mediated MMP-9 activation by Hcy in cultured rat heart microvascular endothelial cells. Our observations suggested that calpain regulates Hcy-induced MMP-9 expression and activity. We showed that Hcy activates calpain-1, but not calpain-2, in a calcium-dependent manner. Interestingly, the enhanced calpain activity was not mirrored by the decreased levels of its endogenous inhibitor calpastatin. We presented evidence that Hcy induces the translocation of active calpain from cytosol to mitochondria, leading to MMP-9 activation, in part, by causing intramitochondrial oxidative burst. Furthermore, studies with pharmacological inhibitors of calpain (calpeptin and calpain-1 inhibitor), ERK (PD-98059) and the mitochondrial uncoupler FCCP suggested that calpain and ERK-1/2 are the major events within the Hcy/MMP-9 signal axis and that intramitochondrial oxidative stress regulates MMP-9 via ERK-1/2 signal cascade. Taken together, these findings determine the novel role of mitochondrial translocation of calpain-1 in MMP-9 activation during HHcy, in part, by increasing mitochondrial oxidative stress.
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PMID:Homocysteine-mediated activation and mitochondrial translocation of calpain regulates MMP-9 in MVEC. 1687 62

Proteolysis by calpain is a unique posttranslational modification that can change integrity, localization, and activity of endogenous proteins. Two ubiquitous calpains, mu-calpain and m-calpain, are highly expressed in the central nervous system, and calpain substrates such as membrane receptors, postsynaptic density proteins, kinases, and phosphatases are localized to the synaptic compartments of neurons. By selective cleavage of synaptically localized molecules, calpains may play pivotal roles in the regulation of synaptic processes not only in physiological states but also during various pathological conditions. Activation of calpains during sustained synaptic activity is crucial for Ca2+-dependent neuronal functions, such as neurotransmitter release, synaptic plasticity, vesicular trafficking, and structural stabilization. Overactivation of calpain following dysregulation of Ca2+ homeostasis can lead to neuronal damage in response to events such as epilepsy, stroke, and brain trauma. Calpain may also provide a neuroprotective effect from axotomy and some forms of glutamate receptor overactivation. This article focuses on recent findings on the role of calpain-mediated proteolytic processes in potentially regulating synaptic substrates in physiological and pathophysiological events in the nervous system.
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PMID:Calpain and synaptic function. 1695 97

Excessive calpain activation contributes to serious cellular damage in many pathological conditions. The involvement of mu-calpain in neurological disorders such as, stroke and Alzheimer's disease has attracted considerable interest in the use of calpain inhibitors as therapeutic agents. 6-Pyridone 2-carboxamides derived from ketoamides were synthesized as conformationally constrained structures resembling the well known peptidic mu-calpain inhibitor, MDL 28,170, and their mu-calpain inhibitory activities were evaluated. Of the compounds synthesized, compound 2a, which has a primary amide at warhead region of the inhibitor most potently inhibited mu-calpain with an IC(50) value of 2.81+/-1.26 microM, which is ca. 40-fold less than that of MDL 28,170.
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PMID:Design and synthesis of calpain inhibitory 6-pyridone 2-carboxamide derivatives. 1839 56

The N-terminal variable region of cardiac troponin T (TnT) is a regulatory structure that can be selectively removed during myocardial ischaemia reperfusion by mu-calpain proteolysis. Here we investigated the pathophysiological significance of this post-translational modification that removes amino acids 1-71 of cardiac TnT. Working heart preparations were employed to study rat acute myocardial infarction and transgenic mouse hearts over-expressing the N-terminal truncated cardiac TnT (cTnT-ND). Ex vivo myocardial infarction by ligation of the left anterior descending coronary artery induced heart failure and produced cTnT-ND not only in the infarct but also in remote zones, including the right ventricular free wall, indicating a whole organ response in the absence of systemic neurohumoral mechanisms. Left ventricular pressure overload in mouse working hearts produced increased cTnT-ND in both ventricles, suggesting a role of haemodynamic stress in triggering an acute whole organ proteolytic regulation. Transgenic mouse hearts in which the endogenous intact cardiac TnT was partially replaced by cTnT-ND showed lowered contractile velocity. When afterload increased from 55 mmHg to 90 mmHg, stroke volume decreased in the wild type but not in the transgenic mouse hearts. Correspondingly, the left ventricular rapid-ejection time of the transgenic mouse hearts was significantly longer than that of wild type hearts, especially at high afterload. The restricted deletion of the N-terminal variable region of cardiac troponin T demonstrates a novel mechanism by which the thin filament regulation adapts to sustain cardiac function under stress conditions.
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PMID:Restricted N-terminal truncation of cardiac troponin T: a novel mechanism for functional adaptation to energetic crisis. 1855 68

The involvement of mu-calpain in neurological disorders, such as stroke and Alzheimer's disease has attracted considerable interest in the use of calpain inhibitors as therapeutic agents. 4-Aryl-4-oxobutanoic acid amide derivatives 4 were designed as acyclic variants of mu-calpain inhibitory chromone and quinolinone derivatives. Of the compounds synthesized, 4c-2, which possesses a 2-methoxymethoxy group at the phenyl ring and a primary amide at the warhead region most potently inhibited mu-calpain (IC(50)=0.34 microM). Our findings suggest that the 4-aryl-4-oxobutanoic acid amide derivatives should be considered as a new family of mu-calpain inhibitors.
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PMID:Design and synthesis of 4-aryl-4-oxobutanoic acid amides as calpain inhibitors. 1904 Dec 42

In vitro nitric oxide (NO) regulates calpain and caspase-3 activation, and in vivo neuronal nitric oxide synthase (nNOS), calpain and caspase-3 participate in the ischemic brain injury. Our objective was to investigate whether nNOS was involved in the ischemic brain injury through activating calpain and caspase-3 during experimental stroke. Rats received 1-h ischemia by intraluminant filament, and then reperfused for 23h (R 23h). nNOS inhibitor 7-nitroindozale (7-NI, 50mg/kg) was administrated intraperitoneally 5min before ischemia. Our data showed that treatment with 7-NI markedly reduced neurological deficits, the brain swelling, and the infarct volume at R 23h. Enzyme studies revealed significant suppression of the activities of m-calpain and caspase-3 in penumbra and core, and the activities of mu-calpain in penumbra, but not in core, in 7-NI-treated rats versus vehicle-treated rats. Western blot analysis demonstrated that 7-NI markedly increased the levels of MAP-2 and spectrin in penumbra and core compared with vehicle-treated rats. Histopathological studies displayed that 7-NI significantly reduced the necrotic cell death in penumbra and core, and apoptotic cell death in penumbra, but not in core. These data demonstrate the involvement of NO produced by nNOS in the ischemic neuronal injury through affecting the activation of calpain and caspase-3 in penumbra and core after experimental stroke, which provides a new perspective on possible mechanisms of action of nNOS inhibition in cerebral ischemia.
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PMID:Inhibition of nNOS reduces ischemic cell death through down-regulating calpain and caspase-3 after experimental stroke. 1916 6

The blood-brain barrier (BBB) consists of dense contacts between endothelial cells, the tight junctions, which are complemented by membrane-bound transporters belonging to the ATP-binding cassette (ABC) transporter family. Liver X receptors (LXR) have previously been shown to stabilize the integrity of atherosclerotic noncerebral arteries. Their effects on ischemic cerebral vessels are still unknown. By delivering LXR agonists, T0901317 and GW3965, to mice submitted to 30 minutes intraluminal middle cerebral artery occlusion, we show that LXR activation reduces brain swelling and decreases BBB permeability by upregulating LXR's target calpastatin that deactivates calpain-1/2, stabilizing p120 catenin. p120 catenin specifically interacts with RhoA and Cdc42, inactivating the former and overactivating the latter, thus restoring the postischemic expression, phosphorylation and interaction of the tight junction proteins occludin and zona occludens-1. Moreover, LXR activation deactivates matrix metalloproteases-2/9 and inhibits microvascular apoptosis by deactivating JNK1/2 and caspase-3. In addition to the cholesterol transporters ABCA1 and ABCG1, which have previously been shown to be upregulated by LXR in noncerebral vessels, LXR activation increases the abundance of the drug transporters ABCB1 and ABCC1 on ischemic brain capillaries, as we further show. That LXR activation promotes endothelial integrity in different ways makes this receptor attractive as target for stroke therapies.
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PMID:Liver X receptor activation enhances blood-brain barrier integrity in the ischemic brain and increases the abundance of ATP-binding cassette transporters ABCB1 and ABCC1 on brain capillary cells. 2176 21

Control of GABA neurotransmission at the pre-synaptic site occurs substantially through the activation of the glutamic acid decarboxylase (GAD) enzymes GAD65 and GAD67. Concentrations of GAD65 and GAD67 are controlled either by transcription or by mRNA splicing and importantly the activities of these key enzymes are regulated by post-translational mechanisms. Important post-translational modifications include proteolytic cleavage, phosphorylation and palmitoylation. A truncated form of GAD65 (tGAD65) is more active than full length GAD65 (fGAD65) whereas, by contrast, truncated GAD67 (tGAD67) is less active than full length GAD67 (fGAD67). The protein responsible for cleaving of fGAD65 and fGAD67 is mu-calpain. GABA neurotransmission is dependent upon whether GAD is associated with synaptic vesicles (SV) and calpain performs a vital role by generating the highly active tGAD65 resulting in augmented GABA synthesis and wrapping uptake into SV. Studies on GAD phosphorylation demonstrate that GAD65 is regulated through phosphorylation by PKC while GAD67 is inhibited through phosphorylation by PKA. Cysteine residues 455 and 446 in GAD67 and GAD65 individually are critical for full GAD regulation. Interaction with the cofactor pyridoxal 50-phosphate (PLP) at this these respective locations regulate the switch between PLP-bound active holoGAD and an unbound active apoGAD form. Transient switching to the PLP bound active holoGAD is integral to GABA neurotransmission. Specific to GAD65 but not GAD67 is palmitoylation by HIP14 which facilitates GAD65 anchoring to SV and enhances the contribution of vesicular GABA to neurotransmission. From studies on a rodent stroke model calpain-mediated cleavage of GAD enzyme has been shown to occur under pathological conditions resulting in less SV refilling and depletion of existing pools of SV releasable GABA.
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PMID:Regulation of GABA Neurotransmission by Glutamic Acid Decarboxylase (GAD). 2637 50


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