Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Calpain, an inactive proenzyme, translocates from the cytosol to the membrane upon binding calcium, and is activated at the membrane in the presence of calcium and PIP2. Activated calpain is very unstable and presumably used only once. Thus the primary targets of calpain are considered to be membrane or membrane-associated proteins. Activation of protein kinase C (PKC) occurs concomitantly with calpain at the membrane. Calpain hydrolyzes only the active PKC species leading to downregulation. Calpain participates in the transcriptional regulation by controlling the levels of transcription factors, c-Jun and c-Fos. The calpain gene is a TPA-responsive gene and its expression is stimulated by activation of PKC. Modulation of cellular signal transduction by controlling the levels of the component proteins, such as PKC, c-Jun and c-Fos is one of the important physiological roles of calpain.
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PMID:Modulation of cellular signals by calpain. 133 90

Administration of beta-adrenergic agonists to mammals can produce skeletal muscle hypertrophy in some species and muscle types. The growth-promoting effect appears to be due to suppression of protein breakdown rather than stimulation of synthesis, although evidence from turnover studies is equivocal. In ovine muscle, changes in the activity of the calcium dependent neutral proteinases (calpains I and II) and their specific inhibitor (calpastatin) accompany beta-agonist-induced hypertrophy. These observations suggest that the calpain system is involved in myofibrillar protein turnover in some way. Alternatively, the relationship with hypertrophy may be indirect, since the calpains also interact with hormone and growth-factor receptors, protein kinase C and transcription factors, in addition to a range of membrane, cytoskeletal and nuclear proteins. In the present study, attempts have been made to determine if the beta-agonist-induced effects on the calpain system are associated with corresponding changes in specific mRNA. The activity of both calpain isoforms and calpastatin was measured in bovine longissimus dorsi samples from trials in which test animals were treated with the beta agonist cimaterol. Total RNA was extracted from the muscle samples. A cDNA probe for calpastatin mRNA was generated from bovine RNA by the polymerase chain reaction. This cDNA and a human calpain-II large-subunit cDNA were used to detect specific mRNA by Northern-blot analysis. beta-agonist treatment of Friesian steers caused significant longissimus dorsi hypertrophy. Increases in muscle mass (+37%, P less than 0.005), calpain-II specific activity (+27%, P less than 0.05) and calpastatin-specific activity (+76%, P less than 0.05) were found in treated animals. Total RNA was unchanged, but there was a 96% overall increase in calpastatin mRNA and a 30% increase in calpain-II large-subunit mRNA in muscle from treated animals. The mRNA changes are similar in direction and degree to the activity changes. Both calpain-II large subunit and inhibitor expression may therefore be stimulated by agonist action at the level of transcription or mRNA stabilisation. Multiple calpastatin mRNA species were detected in steers, as reported for other species. Differential changes in these messages, induced by the beta agonist, suggest that expression or stability of alternative mRNA species may be a factor in calpastatin regulation.
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PMID:Changes in calpain and calpastatin mRNA induced by beta-adrenergic stimulation of bovine skeletal muscle. 135 30

Vasospasm was produced in adult mongrel dogs by a two-hemorrhage method, and the spastic basilar arteries were exposed via the transclival route on Day 7. Tonic contraction was produced in the normal canine basilar arteries by a local application of KCl or serotonin after transclival exposure. The exposed spastic and tonic basilar arteries then received a topical application of the following: 1-(5-isoquinolinesulfonyl)-2-methyl-piperazine (H-7), a potent inhibitor of protein kinase C acting at the catalytic domain; calphostin C, a specific inhibitor of protein kinase C acting at the regulatory domain; or calpeptin, a selective inhibitor of calpain. Both spastic and tonic basilar arteries were effectively dilated by H-7. Calphostin C caused only slight dilation of spastic basilar arteries but moderate dilation of tonic basilar arteries. Dilation in response to calpeptin was remarkable in the spastic basilar arteries but slight in the tonic basilar arteries. The doses of calphostin C and calpeptin required to obtain maximum effect were markedly lower in the tonic model than in the spastic model. The spastic and tonic models had a similar dose-dependent response to H-7 but quite a different response to calphostin C or calpeptin, suggesting a difference in the function of protein kinase C and calpain in the two models. Furthermore, the effect of calphostin C on the reversal of vasospasm was increased significantly after topical treatment with calpeptin. It is suggested that the majority of the catalytic domain of protein kinase C is dissociated from the regulatory domain, probably by a limited proteolysis with calpain, and is markedly activated in vasospasm.
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PMID:Effects of inhibitors of protein kinase C and calpain in experimental delayed cerebral vasospasm. 137 69

Using a calpain/protein kinase C (PKC) complex, we were able to reproduce, in vitro, the induction of PKC down-regulation by the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA) which had been previously observed in cells. We show that TPA initiates this phenomenon by promoting a calpain-dependent conversion of PKC to the Ca2+ phospholipid-independent protein kinase M (PKM), at physiological calcium concentrations. This effect of TPA was dependent upon the presence of phosphatidylserine and was observed only when PKC was the substrate for the protease, inactivation of calpain by autolysis not being modified by the presence of TPA. Moreover, PKM generated from the calpain-PKC complex was resistant to calpain, even after addition of TPA. These results suggest that TPA induces a conformational change in PKC, increasing the affinity of the kinase for calpain and consequently permitting its proteolysis for the basal level of calcium in cells.
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PMID:Induction of protein kinase C down-regulation by the phorbol ester TPA in a calpain/protein kinase C complex. 139 15

Long-term potentiation (LTP) is an experimental model for memory and learning in higher animals. It is a well-known fact that intracellular rise in Ca2+ is an essential requirement for generation of LTP. Little is known about the synaptic modulation triggered by the intracellular Ca2+ rise, though the involvement of protein kinase C, Ca2+/calmodulin-dependent protein kinase II (CaM KII), and/or calpain are indicated experimentally. For the purpose of making the synaptic change clearer we tried to characterize the substrates for the protein kinases associated with isolated postsynaptic density (PSD)-enriched fractions. Four major groups of substrates for the CaM KII (250 k M(r), 200 k M(r), 180 k M(r), and 140 k M(r)) and one for kinase C (17 k M(r)) were identified. The 250 k M(r) substrate resembled P400 protein, IP3 receptor, in structure. The 17 k M(r) substrate was different from myelin basic protein which was electrophoresed nearly at the same distance. We made an antibody against the 140 k M(r) substrates to obtain biological and physicochemical properties of the protein. We also made an antibody specific to the Thr286-autophosphorylated and autonomous form of CaM KII. The latter antibody is an extremely useful reagent to understand the biological functions of the CaM KII, especially the role of autophosphorylation of the kinase in modulation of the synaptic function such as in LTP.
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PMID:[Postsynaptic mechanism of long-term potentiation]. 141 33

Both an enhancement of Ca(2+)-independent kinase activity in the supernatant fraction and enhanced breakdown of type beta kinase C (PKC-beta) were observed in the hippocampus after induction of tetanus-induced long-term potentiation (LTP) in the hippocampal CA1 region of rat. The enhanced activity was inhibited by the PKC-specific inhibitor, PKC19-36. Both phenomena were also observed simultaneously in the in vitro model system in which hippocampal homogenate was treated with CaCl2, and both enhancements were inhibited by the addition of calpain inhibitors, leupeptin and benzyloxycarbonyl-Leu-Met-H. The results suggest that Ca(2+)-independent kinase activity enhanced in the supernatant fraction during LTP derives from the catalytic fragment of PKC-beta released by calpain.
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PMID:Calpain may produce a Ca(2+)-independent form of kinase C in long-term potentiation. 148 63

The Ca2+ ion exerts a profound influence on cellular processes and an understanding of control mechanisms of intracellular Ca2 homeostasis while complex is mandatory in this discussion. The identification and recognition of prolonged sustained increase in [Ca2+]i as a manifestation of neurotoxin-induced destabilization of [Ca2+]i homeostasis will be related to a variety of neurotoxicant-induced cell injuries. The sites of toxicant interaction with ATP-regulated Ca2+ pumps located in the neuronal/glial membrane and/or calciosomes; availability of Ca2+ proteins; disruption in mitochondrial mechanisms for Ca2+ storage; triggers of voltage-dependent Ca2+ channels and modulation of the Na+/Ca2+ exchanger will be identified and related to presumptive toxin action. Failure of one or more of these systems will result in continuous elevation of ionized [Ca2+]i--a reflection of Ca2+ destabilization. The targets resulting from Ca2+ destabilization will be identified, to include phospholipase C activation, PLA2 activation, protein kinase C (PKC) translocation, and activation of Ca(2+)-dependent calpain 1. The use of specific inhibitors of neurotoxicity, e.g., natural sphingolipids, sphingosine, down regulation of PKC, inhibitors and activators of adenylate cyclase, and antiprotease agents will allow for investigation of the role of these final common pathways in the evolution of neurotoxicity.
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PMID:Ca(2+)-dependent processes as mediators of neurotoxicity. 150 13

Treatment of rat brain slices with veratrine and monensin decreased (Na+ + K+)-ATPase activity in the membranes in a dose-dependent manner. The effect of monensin, like that of veratrine, was accompanied by a decrease of maximal binding sites for ouabain. The inhibitory effect of monensin on the enzyme activity was dependent on external Ca2+ at low concentrations, but not at a high concentration. The decreased enzyme activity induced by monensin was restored by subsequent incubation of the slices in a Ca(2+)-free medium containing 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetraacetoxymethyl ester (BAPTA-AM), a chelator of intracellular Ca2+. The effect of monensin at a low concentration on enzyme activity was antagonized by amiloride (1 mM), bepridil (5 microM), quinacrine (30 microM) or verapamil (30 microM), but not by nifedipine (1 microM) or omega-conotoxin (1 microM). Furthermore, the inhibitory effect of monensin at a high concentration under Ca(2+)-free conditions was blocked by BAPTA-AM (30 microM) and by bepridil (100 microM) or diazepam (500 microM), inhibitors of mitochondrial Na(+)-Ca2+ exchange. Inhibitors of calmodulin, protein kinase C, phospholipase A2 and calpain did not affect the monensin-induced decrease of enzyme activity. Dithiothreitol (10 mM) blocked the effect of monensin on enzyme activity but did not affect the ionophore-induced influx of Ca2+ in the slices.
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PMID:Na+ influx-induced decrease of (Na+ + K+)-ATPase activity in rat brain slices: role of Ca2+. 166 55

The effect of acidic phospholipids on proteolysis of protein kinase C (PKC) by mu-calpain was examined at Ca++ concentrations ranging from 10(-7) to 10(-4) M. The gamma species, among the molecular species of PKC, was more susceptible to calpain than the alpha and beta (beta I/beta II) and was hydrolysed at Ca++ concentrations greater than or equal to 10(-6) M. Acidic phospholipids enhanced proteolysis of PKC gamma and lowered Ca++ concentrations required for it to the level below 10(-6) M. Among the phospholipids tested, phosphatidylinositol-bisphosphate showed the most prominent effect; phosphatidylinositol and phosphatidylserine were less effective. Polyphosphoinositides, hence, may constitute an essential structure in cell membranes for positive regulation of calpain activity.
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PMID:Proteolysis of protein kinase C by calpain: effect of acidic phospholipids. 166 83

Synaptosomes prepared from brain tissues are known to retain morphological and functional characteristics of the nerve ending. Little information is available, however, as to the biochemical events underlying synaptogenesis and transmitter release. Increasing body of evidence suggests that protein kinase C (PKC) plays crucially important roles through phosphorylation of membrane proteins such as GAP-43 (for 43-kDa growth-associated protein) and 87-kDa MARCKS (for myristoylated, alanine-rich C kinase substrate) in many aspects of the neuronal function. Among them, arrangement of membrane cytoskeletal protein is proposed to be one of the primary sites of PKC action. The present study is an attempt to isolate and characterize PKC associated with synaptosomal membrane cytoskeleton. Rat brain synaptosomal Triton X-100 insoluble elements (cytoskeleton) contains specific [3H]phorbol dibutyrate binding activity and 78-kDa protein which reacts with an antibody against beta II-PKC subspecies. Although 78-kDa protein could not be solublized by the treatment with various ionic and non-ionic detergents and/or high concentrations of salts such as NaCl and LiBr, the fragment of 78-kDa protein was produced and solublized from cytoskeleton by limited proteolysis with calpain II, which cleaves PKC at one or two specific sites of the enzyme to produce catalytic and regulatory fragments. The solubilized 46-kDa fragment was identical with the catalytic fragment of beta II-PKC. The results indicate that this PKC subspecies is tightly associated with the cytoskeletal network of synaptic membranes.
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PMID:Isolation and characterization of protein kinase C from rat brain synaptosome cytoskeleton. 174 42


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