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

1. Rat liver microsomal membranes were studied for the presence of protein kinases. Microsomal proteins solubilized with Triton X-100 were analyzed by means of ion exchange chromatography. 2. Protein kinase activity was detected in the column fractions using specific assays for cAMP-dependent protein kinase, cGMP-dependent protein kinase, protein kinase C, Ca2+/calmodulin-dependent protein kinase and casein kinases. 3. Fractions with protein kinase activity were further analyzed by SDS-polyacrylamide gel electrophoresis. 4. The results indicate that cAMP-dependent protein kinase type I and II, casein kinases I and II, protein kinase C proenzymes I and II and Ca2+/calmodulin kinase II are associated with the membranes of endoplasmic reticulum (ER).
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PMID:Rat liver endoplasmic reticulum protein kinases. 818 36

Protein kinase isoenzymes belonging to the protein kinase C (PK-C) family present in rat mammary tissue have been resolved from one another by chromatography on hydroxyapatite, and characterized. PK-C alpha is the predominant isoenzyme and is present at a constant level of activity throughout mammary-gland development and differentiation. In contrast, marked changes in the relative abundance of other mammary PK-C isoenzymes accompany the transition from pregnancy to lactation. The sensitivity of mammary PK-C alpha to Ca2+ is greater in tissue from pregnant than from lactating rats. This isoenzyme has other atypical properties consistent with its being more highly phosphorylated than PK-C alpha in rat brain and spleen. One of the protein kinase isoenzymes resolved from mammary tissue recognizes the peptide substrate used to assay AMP-activated kinase and may thus interfere in the determination of this activity. Another is fully active in the absence of Ca2+ and is more than 80% active in the absence of added lipid effectors. A 'housekeeping' role is proposed for PK-C alpha in mammary tissue, whereas the less abundant PK-C isoenzymes may be involved in mammary cell proliferation and differentiation.
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PMID:Isoenzymes of protein kinase C in rat mammary tissue: changes in properties and relative amounts during pregnancy and lactation. 848 8

Incubation of intact U-937 cells with 1 micron [gamma-32P] ATP resulted in rapid (10 min) incorporation of radioactivity into phosvitin, kemptide and protein kinase C (PKC)-peptide. The amount of incorporation was dependent on substrate type and concentration, and on incubation time. Staurosporine, H-7 and Mg(2+)-exclusion abolished phosphorylation of kemptide and PKC-peptide but not phosvitin. Cyclic AMP and phorbol ester enhanced kemptide and PKC-peptide phosphorylation. Protein kinase inhibitor (PKI) inhibits only kemptide phosphorylation. Cell differentiation enhanced 2-fold the phosphorylation of phosvitin and PKC-peptide without significant effect on kemptide phosphorylation. ATP concentrations sufficient to trigger changes in intracellular Ca2+ were sufficient to support extracellular phosphorylation reactions. The results suggest the presence of at least three ectokinase activities on U-937 cells that may play important roles in regulating membrane associated specific functions of developing and mature monocytes.
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PMID:Ectoprotein kinase activities on non-differentiated and differentiated U-937 cells. 852 11

1. Protein kinase modulation of gamma-aminobutyric acid-A (GABAA)- and glycine-activated Cl- currents in freshly dissociated, morphologically identified rabbit retinal rod bipolar cells was studied under voltage clamp with the use of the whole cell patch-clamp technique. Responses to pulses of GABA and glycine were monitored before, during, and after application of adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase (PKA) and protein kinase C (PKC) activators, inactive analogues, and inhibitors. 2. Bath perfusion with either forskolin, an adenylate cyclase activator, or its inactive analogue, 1,9 dideoxyforskolin, reduced the GABA-activated Cl- currents by 30-50%; coapplication of N-[2-(Methylamino)ethyl]-5-isoquinolinesulfonamide hydrochloride (H-8), a PKA inhibitor, did not prevent the forskolin effects. The membrane-permeable cAMP analogues, 8-bromo-cAMP and 8-(4-Chlorophenylthio)-cAMP, and intracellularly dialyzed cAMP, did not modulate either the GABA- or glycine-activated Cl- current. Perfusion of the phosphodiesterase inhibitor 3-isobutyl-1-methylxantine (IBMX) had no direct effect on the GABA-activated current and did not alter the results with cAMP or its membrane-permeable analogues. Collectively, these results make it very unlikely that PKA represents an important mechanism of either GABAA or glycine channel modulation in the rabbit rod bipolar cell. 3. Although the isoquinoline sulfonamide protein kinase inhibitor H-8 was without discernible effect, the related compounds 1-(5-Isoquinolinesulfonyl)-2-methylpiperazine dihydrochlorine (H-7) and N-(2-Aminoethyl)-5-isoquinolinesulfonamide dihydrochloride (H-9) both dramatically reduced the GABA response. H-7 also strongly reduced the response to glycine, whereas H-8 had no effect and H-9 had an intermediate effect. Because only certain members of this inhibitor class of agents proved effective, and their effectiveness appeared unrelated to the established activity profiles, these agents probably inhibit the Cl- currents in a phosphorylation-independent manner. Direct interaction of these inhibitors with binding sites in the GABAA receptor-channel complex has been previously reported in some other preparations. 4. The phorbol ester and PKC activator phorbol 12,13 dibutyrate (PDB) led to a 35-55% reduction in the GABA-activated Cl- current of the rod bipolar cell. The broad-spectrum kinase inhibitor staurosporine, and the more PKC-specific inhibitor calphostin C, had no direct effect on GABA responses, but prevented Cl- current reduction when coapplied with PDB. Phorbol 12-myristate 13-acetate (PMA) reduced the GABA-activated current in a fashion very similar to PDB. Staurosporine and calphostin C blocked the PMA effect. No reduction of Cl- current was seen with the inactive analogue, 4-alpha-PMA, used as a control for PKC-independent phorbol ester effects. 5. PDB effectively reduced the GABA-activated Cl- current of the rod bipolar cell at low concentrations, whereas PMA had a diminished effect at low concentrations. This is consistent with the reported concentration-dependent abilities of these agents to promote translocation of PKC-alpha immunoreactivity from the membrane to the cytosolic compartment in the rabbit retinal rod bipolar cell. Collectively, the data from phorbol esters, inactive analogues, and kinase inhibitors support the existence of a PKC-mediated mechanism for GABA-activated Cl- current reduction in these cells. 6. The naphthalenesulfonamide PKC activator N-(n-Heptyl)-5-chloro-1-naphthalenesulfonamide (SC-10) also potently and reversibly reduced the GABA-activated current. Staurosporine and calphostin C eliminated this effect. When the nonhydrolyzable guanosine 5'-triphosphate (GTP) analogue guanosine 5'-O-(3-thiotriphosphate) tetralithium salt (GTP-gamma-S) replaced GTP in the recording pipette, the SC-10-mediated GABA current reduction became irreversible.(ABSTRACT TRUNCATED)
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PMID:Protein kinase modulation of GABAA currents in rabbit retinal rod bipolar cells. 893 Feb 56

Protein kinase activators as well as several neuropeptides are able to increase the GnRH-binding capacity of cultured adenohypophyseal cells. To determine whether such up-regulation of GnRH-binding sites can be achieved by a substance(s) endogenous to the pituitary, binding experiments were performed after exposure of cells to increasing amounts of medium conditioned by incubation with primary cultures of adenohypophyseal cells for 4 days. Addition of the conditioned medium elicited a 50% increase in GnRH binding. Characterization of the agent(s) responsible for the effect was attempted by submitting the conditioned medium to molecular sieve filtration, adding or immunoprecipitating endogenous substances, and comparing the susceptibilities of the responses to various inhibitors of transduction processes. Fractionation of the medium indicated that active molecules were of a proteic nature, with M(r) ranging from 5,000-10,000. Among major endogenous moieties corresponding to these criteria [epidermal] growth factor (EGF), transforming growth factor-alpha, and insulin-like growth factors I and II), only the first two exhibited properties similar to those of the conditioned medium. EGF stimulated binding with an EC50 of 3.6 +/- 0.8 pM. Immunoprecipitation of EGF, but not transforming growth factor-alpha, inactivated the conditioned medium. The effects of both conditioned medium and EGF were inhibited by herbimycin, a tyrosine kinase inhibitor; U73122, a phospholipase C inhibitor; and prior desensitization of protein kinase C. In contrast, both were insensitive to pertussis toxin pretreatment. In parallel, EGF did not increase LH secretion by itself, but potentiated its response to GnRH in a concentration range of 1 pM to 1 nM, resulting in a shift of the curve toward lower values of GnRH. It is concluded that EGF is able to control the accessibility of binding sites to GnRH and to potentiate the responsiveness of gonadotropes to the decapeptide.
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PMID:Cryptic gonadotropin-releasing hormone receptors of rat pituitary cells in culture are unmasked by epidermal growth factor. 900 88

1. The superior colliculus (SC)/optic tectum is a multi-layered midbrain area that harbours representations of visual and auditory space and somatic body surface. The development and maintenance of these sensory maps has been shown to involve activity and experience-dependent mechanisms. 2. The implantation of an extra eye primordium into the developing forebrain of Rana pipens results in the formation of dually innervated tecta that would have normally be solely innervated by the contralateral retina. The retinal projections are arranged in an interdigitating pattern of alternate stripes of terminations from each retina. The establishment of this striped pattern requires retinal activity and depends on N-methyl-D-aspartate (NMDA) receptors. Manipulation of protein kinase activity leads to the formation of an abnormal stripe pattern. 3. Regeneration of the goldfish retinotectal projection, following crush of the optic nerve, occurs in an activity dependent manner involving NMDA receptors. Furthermore, a critical period exists, during which retinal activity is vital for reformation of the visual map. Protein kinase manipulations during this period disrupt normal reformation. The same manoeuvres at other time points have little effect on map reformation. 4. An unusual form of long-term potentiation (SC-LTP) has been demonstrated in the in vitro preparation of the guinea-pig SC. By stimulating the optic layer of the SC, a postsynaptic potentiation can be recorded in the superficial grey layer. The expression of SC-LTP is masked but not prevented by blockade of NMDA receptors. The role of protein kinases in this form of synaptic modification has also been studied using various manipulations and inhibitors with varying substrate specificity. Whereas H7, an inhibitor reputed to be protein kinase C specific, only masks the expression of SC-LTP, K252a which has a broad substrate specificity blocks the induction of SC-LTP. 5. Experience-dependent formation of the auditory space map in the deeper layers of the SC is believed to be under the instruction of the visual representation in the superficial layers. Furthermore, a crucial period exists during which normal auditory and visual experience are required for successful establishment of the auditory map. Chronic exposure to 5-aminophosphonopentanoic acid (AP5) during this time prevents the formation of the map. Chronic exposure to K252a, a broad kinase inhibitor, over the same time period, also disrupts the formation of the auditory space map. 6. Taken together, these models emphasise the role of protein kinases in synaptic plasticity observed in the SC. Furthermore, interference with protein kinase activity at crucial stages of regeneration or development appears to disrupt the sequence of events that lead to the consolidation of SC receptive fields.
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PMID:The contribution of protein kinases to plastic events in the superior colliculus. 915 64

Protein kinase inhibitors staurosporine and CGP 41251, a benzoylated derivative of staurosporine with selective PKC inhibitory activity, reversed the decreased rhodamine 123 uptake in HL-60/VCR (with Pgp-mediated drug resistance) but not in HL-60/ADR (MRP-mediated drug resistance) cells. CGP 41251 reversed the decreased rhodamine 123 uptake in HL-60/VCR cells more efficiently (when compared on a equimolar basis) than staurosporine. However, the protein tyrosine kinase inhibitor genistein unexpectedly modulated the decreased rhodamine 123 uptake in Pgp positive (HL-60/VCR) cells, but not in HL-60/ADR (MRP positive) cells. Cell surface phenotype of both HL-60 drug-resistant cell sublines was compared with that of the parental, drug-sensitive HL-60 cells. Both drug-resistant cell lines expressed markedly decreased levels of cell surface HLA class I antigen in comparison with the parental HL-60 cells. A similar decreased cell surface expression of HLA class II/DR on both drug-resistant, as well as of CD59 (protectin) on HL-60/ADR cells was found. Both protein kinase C inhibitors studied (staurosporine and CGP 41251) exhibited variable effects on cell surface antigen (HLA, ICAM-1, CD59) expression, suggesting complex interactions between PKC-dependent and -independent mechanisms in the regulation of surface antigen expression in these cell lines. Staurosporine differed from CGP 41251 in the cell cycle alterations induced in the HL-60 cell lines examined. Staurosporine induced the accumulation of cells in the G2/M phase of the cell cycle and the appearance of pre-G0 (apoptotic) cells in both examined drug-resistant cell lines. Staurosporine induced the appearance of cells with high DNA content in HL-60/ADR, but not in HL-60/VCR cells.
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PMID:Protein kinase inhibitor-induced alterations of drug uptake, cell cycle and surface antigen expression in human multidrug-resistant (Pgp and MRP) promyelocytic leukemia HL-60 cells. 922 74

Protein kinase Cmu is a novel member of the protein kinase C (PKC) family that differs from the other isoenzymes in structural and enzymatic properties. No substrate proteins of PKCmu have been identified as yet. Moreover, the regulation of PKCmu activity remains obscure, since a structural region corresponding to the pseudosubstrate domains of other PKC isoenzymes has not been found for PKCmu. Here we show that aldolase is phosphorylated by PKCmu in vitro. Phosphorylation of aldolase and of two substrate peptides by PKCmu is inhibited by various proteins and peptides, including typical PKC substrates such as histone H1, myelin basic protein, and p53. This inhibitory activity seems to depend on clusters of basic amino acids in the protein/peptide structures. Moreover, in contrast to other PKC isoenzymes PKCmu is activated by heparin and dextran sulfate. Maximal activation by heparin is about twice and that by dextran sulfate four times as effective as maximal activation by phosphatidylserine plus 12-O-tetradecanoylphorbol-13-acetate, the conventional activators of c- and nPKC isoforms. We postulate that PKCmu contains an acidic domain, which is involved in the formation and stabilization of an active state and which, in the inactive enzyme, is blocked by an intramolecular interaction with a basic domain. This intramolecular block is thought to be released by heparin and possibly also by 12-O-tetradecanoylphorbol-13-acetate/phosphatidylserine, whereas basic peptides and proteins inhibit PKCmu activity by binding to the acidic domain of the active enzyme.
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PMID:Regulation of protein kinase Cmu by basic peptides and heparin. Putative role of an acidic domain in the activation of the kinase. 925 96

1. Protein kinase modulation of glycine-activated currents was examined in acutely dissociated ganglion cells from tiger salamander retina using whole-cell voltage-clamp techniques. 2. Glycine (100 microM) induced an outward chloride current in cells clamped at 0 mV. Co-application of 50 microM forskolin made the glycine-induced current more transient. The combination of forskolin and glycine reduced the later portion of current response without changing the initial peak amplitude. 3. 3-Isobutyl-1-methylxanthine (IBMX) or 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP) produced effects similar to those of forskolin. H-89, a protein kinase A (PKA) inhibitor, blocked the effect of forskolin. 4. A protein kinase C (PKC) activator, OAG (1-oleoyl-2-acetyl-sn-glycerol), also made the glycine response more transient. Unlike PKA analogues, OAG enhanced the glycine peak response without changing the glycine late response. OAG effects were blocked by 1 microM GF-109203X, a PKC inhibitor. 5. Nanomolar concentrations of strychnine selectively blocked the fast phase of the glycine current and reversed the effect of OAG, but not that of forskolin. Conversely, forskolin occluded the effect of 5,7-dichlorokynurenic acid, which selectively suppresses the late phase of the glycine current. The action of OAG was not blocked by 5,7-dichlorokynurenic acid. 6. Thus, through a differential modulation, both protein kinase A and C shorten the decay time of the glycine current. PKA suppresses the slow component, while PKC potentiates the fast component.
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PMID:Protein kinases modulate two glycine currents in salamander retinal ganglion cells. 951 25

beta2-Adrenergic receptors (beta2ARs) are important regulators of airway smooth muscle tone, and beta-sympathomimetic drugs are the most widely used agents in asthma therapy and are universally recognized as the treatment of choice for acute asthma attacks. Despite the clinical importance of beta-agonists and a good understanding of their mechanism of action in airway smooth muscle relaxation, surprisingly little is known about the manner in which the beta2AR signaling pathway is regulated in human airway smooth muscle (HASM). In this communication, we characterize mechanisms underlying rapid desensitization of the HASM beta2AR-adenylyl cyclase (AC) pathway. Acute homologous desensitization of beta2AR-mediated cyclic adenosine monophosphate (cAMP) production was characterized by an approximately 60% loss of maximal responsiveness to isoproterenol (ISO) when cells were pretreated for 30 min with 1 microM ISO. Acute heterologous beta2AR desensitization was characterized by an approximately 20% and 30% loss of maximal responsiveness to ISO challenge when cells were pretreated with forskolin and prostaglandin E2 (PGE2), respectively. Each form of desensitization was also characterized by an increase in the EC50 for ISO. beta2AR sequestration was associated with but not required for homologous desensitization. However, sequestration was required for rapid resensitization. Minimal alterations in inherent AC activity were observed with both modes of desensitization, suggesting that the beta2AR is the principal locus of regulation. Protein kinase inhibition by staurosporine largely reversed heterologous beta2AR desensitization and had a small but significant effect on homologous desensitization. In contrast, bisindolylmaleimide IX, a specific PKC-inhibitor, had no effect on heterologous or homologous beta2AR desensitization, suggesting that staurosporine effects were mediated by PKA inhibition. Overexpression of the G protein-coupled receptor kinase GRK2 in HASM cultures enhanced homologous desensitization. These data suggest that HASM beta2ARs are highly susceptible to rapid desensitization by multiple agents, and identify both GRKs and PKA as important mediators of acute beta2AR desensitization.
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PMID:Mechanisms of acute desensitization of the beta2AR-adenylyl cyclase pathway in human airway smooth muscle. 969 8


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