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)

Although the protein kinase C (PKC) activator, phorbol 12-myristate 13-acetate (PMA) has been known to induce heterologous desensitization of the epidermal adenylate cyclase, the precise mechanism of PMA action remains unknown. Effects of PMA on the receptor-G-protein-adenylate cyclase system of fetal rat skin keratinocytes (FRSK) were investigated. Choleratoxin catalysed the ADP ribosylation of 45 kDa and 52 kDa membrane proteins and islet activating protein (IAP) catalysed the ADP ribosylation of a 40 kDa membrane protein. Incubation of FRSK with PMA decreased the cholera toxin-catalysed ADP ribosylation of the membrane protein, but not the IAP-catalysed ADP ribosylation. The effect of PMA on the cholera toxin-catalysed ADP ribosylation was inhibited by the PKC inhibitor, H-7 (1-(5-isoquinolinesulfonyl)-2-methyl piperazine dihydrochloride). 1-Oleoyl-2-acetylglycerol (OAG), a membrane-permeable diacylglycerol analogue, also decreased the cholera toxin-catalysed ADP ribosylation, but 4-0-methyl PMA, a very weak PKC activator, had no effect. Keratinocytes are known to express the guanine nucleotide binding proteins, Gsalpha, Gi2alpha, and Gi3alpha. Immunoblot analysis of the PMA-treated FRSK showed no detectable difference in the amount of Gsalpha, Gi2alpha, Gi3alpha, or the beta subunit of the G-protein. PMA significantly decreased the beta-adrenergic adenylate cyclase response and cholera toxin-induced cyclic AMP accumulation, while it markedly increased forskolin-induced cyclic AMP accumulation. These results indicate that phorbol esters affect the stimulatory guanine nucleotide binding protein (Gs) of FRSK via a PKC-dependent pathway.
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PMID:Protein kinase C-dependent modulation of stimulatory guanine nucleotide binding protein of fetal rat skin keratinocytes. 875 Sep 31

The ability of protein kinase C (PKC) to regulate the responsiveness of adenylyl cyclase to different activators was assessed. Membranes prepared from Sf9 cells infected with recombinant baculoviruses encoding either type II or IV adenylyl cyclase were incubated with recombinant PKCalpha (purified from Sf9 cells), and the effects on adenylyl cyclase activity were measured after reconstitution with Gsalpha, Gbetagamma, or forskolin. PKCalpha treatment of type II adenylyl cyclase leads to increases in basal, forskolin-stimulated, and betagamma-stimulated activities and greater sensitivity to stimulation by Gsalpha. Paradoxically, most of the betagamma potentiation of Gsalpha-stimulated activity is eliminated by pretreatment with PKCalpha. By contrast, treatment of type IV adenylyl cyclase with PKCalpha has little effect on the basal, forskolin-stimulated, or betagamma-stimulated activities but markedly reduces the Gsalpha-stimulated and betagamma-potentiated activity of this isoform. These studies demonstrate that protein kinases can alter both the activity of adenylyl cyclase isoforms and their responsiveness to G protein regulation, thereby altering the ability of adenylyl cyclases to integrate signals derived from multiple hormonal inputs.
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PMID:Protein kinase C alters the responsiveness of adenylyl cyclases to G protein alpha and betagamma subunits. 890 Feb 9

Morphogen-induced decline in Gialpha triggers F9 teratocarcinoma stem cells to progress to primitive endoderm via activation of protein kinase C and mitogen-activated protein kinase (Gao, P., and Malbon, C. C. (1996) J. Biol. Chem. 271, 9002-9008). Constitutive expression of Gialpha2 blocks, whereas expression of Gsalpha provokes, progression to primitive endoderm, permitting identification of the effectors of the response-utilizing chimera created between Gialpha2 and Gsalpha. N-terminal substitution of Gsalpha with Gialpha2 sequence to create chimera Gialpha2 (1-54)/Gsalpha produced a chimera that activated adenylylcyclase but abolished progression to primitive endoderm and activation of phospholipase C. C-terminal substitution of Gsalpha with Gialpha2 sequence to Gsalpha/Gialpha2 (320-355) enhanced the ability of Gsalpha to promote progression. The Q205L-activated mutant of Gialpha2 suppresses, whereas the G225T-activated mutant of Gsalpha strongly activates phospholipase C and progression in these cells. The N-terminal region of Gsalpha (residues 62-86) appears to act as a dominant switch for the Gsalpha- (activation) versus Gialpha2- (suppression) mediated control of phospholipase C and progression to primitive endoderm.
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PMID:Differentiation of F9 teratocarcinoma stem cells to primitive endoderm is regulated by the Gialpha2/Gsalpha axis via phospholipase C and not adenylylcyclase. 894 46

Adenosine exerts a mitogenic effect on human endothelial cells via stimulation of the A2A-adenosine receptor. This effect can also be elicited by the beta2-adrenergic receptor but is not mimicked by elevation of intracellular cAMP levels. In the present work, we report that stimulation of the A2A-adenosine receptor and of the beta2-adrenergic receptor activates mitogen-activated protein kinase (MAP kinase) in human endothelial cells based on the following criteria: adenosine analogues and beta-adrenergic agonists cause an (i) increase in tyrosine phosphorylation of the p42 isoform and to a lesser extent of the p44 isoform of MAP kinase and (ii) stimulate the phosphorylation of myelin basic protein by MAP kinase; (iii) this is accompanied by a redistribution of the enzyme to the perinuclear region. Pretreatment of the cells with cholera toxin (to down-regulate Gsalpha) abolishes activation of MAP kinase by isoproterenol but not that induced by adenosine analogues. In addition, MAP kinase stimulation via the A2A-adenosine receptor is neither impaired following pretreatment of the cells with pertussis toxin (to block Gi-dependent pathways) nor affected by GF109203X (1 microM; to inhibit typical protein kinase C isoforms) nor by a monoclonal antibody, which blocks epidermal growth factor-dependent signaling. In contrast, MAP kinase activation is blocked by PD 098059, an inhibitor of MAP kinase kinase 1 (MEK1) activation, which also blunts the A2A-adenosine receptor-mediated increase in [3H]thymidine incorporation. Activation of the A2A-adenosine receptor is associated with increased levels of GTP-bound p21(ras). Thus, our experiments define stimulation of MAP kinase as the candidate cellular target mediating the mitogenic action of the A2A-adenosine receptor on primary human endothelial cells; the signaling pathway operates via p21(ras) and MEK1 but is independent of Gi, Gs, and the typical protein kinase C isoforms. This implies an additional G protein which links this prototypical Gs-coupled receptor to the MAP kinase cascade.
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PMID:Stimulation of the mitogen-activated protein kinase via the A2A-adenosine receptor in primary human endothelial cells. 903 93

To define the integration of multiple signals by different types of adenylyl cyclase (AC) within the cell, we altered the population of enzymes expressed in the cell and determined the subsequent processing of stimulatory and inhibitory input. DDT1-MF2 cells expressed AC VI-IX and were stably transfected with AC II, III, or IV. Enzyme expression was confirmed by RNA blot analysis and functional assays. Basal enzyme activity was only increased in AC II transfectants (6-fold). Maximum stimulation of enzyme activity was increased in each of the AC transfectants to varying extents. alpha2A/D-AR activation elicited enzyme type-specific responses. alpha2-AR activation inhibited the effect of isoproterenol in control transfectants, and this action was magnified in AC III transfectants. In AC II and AC IV transfectants, alpha2-AR activation initiated both positive (Gbetagamma) and negative signals (Gialpha) to the Gsalpha-stimulated enzyme, and both types of signals were blocked by cell pretreatment with pertussis toxin. The negative input to AC II from the alpha2-AR was blocked by protein kinase C activation in AC II transfectants, but it was the positive input to AC IV that was compromised by protein kinase C activation. These data indicate that the integration of multiple signals by adenylyl cyclases is a dynamic process depending upon the enzyme type and phosphorylation status.
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PMID:Factors determining the specificity of signal transduction by guanine nucleotide-binding protein-coupled receptors. Integration of stimulatory and inhibitory input to the effector adenylyl cyclase. 919 55

The localization of the nine identified isoforms of adenylyl cyclase in brain has been largely based on determination of patterns of mRNA expression. A polyclonal antibody has now been developed that specifically recognizes Type VII adenylyl cyclase. This antibody was used for immunocytochemical analysis of the distribution of Type VII adenylyl cyclase in rat brain. Labeling of Type VII adenylyl cyclase was observed in several areas, including cerebellum, caudate-putamen, nucleus accumbens, hippocampus and cerebral cortex. In some of these areas, the staining of the adenylyl cyclase protein suggested the possibility of presynaptic localization. For example, in situ hybridization showed Type VII adenylyl cyclase mRNA concentrated in cerebellar granule neurons. The cerebellar granule cell layer, however, showed little immunostaining, while punctate immunostaining was observed in the molecular layer. These results suggested that protein synthesized in the granule neurons may be targeted to the neuron terminals. Punctate staining in the caudate-putamen, globus pallidus and nucleus accumbens also suggested the possibility of axonal and/or dendritic localization of Type VII adenylyl cyclase in these regions. Labeling of the soma of cerebellar Purkinje cells, cortical pyramidal and non-pyramidal cells and interneurons in the cerebellum and hippocampus was also observed. Type VII adenylyl cyclase, like the other adenylyl cyclase isoforms, has distinct regulatory characteristics, including sensitivity to stimulation by Gsalpha and G protein betagamma subunits, modulation by protein kinase C, and high sensitivity to stimulation by ethanol. These characteristics, and the discrete localization of this enzyme, may contribute to its ability to provide signal integration and/or control of neurotransmitter release in particular neurons or brain areas.
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PMID:Immunological assessment of the distribution of type VII adenylyl cyclase in brain. 955 42

Circadian functions of the suprachiasmatic nuclei (SCN) are influenced by cyclic AMP (cAMP). Adenylyl cyclase type II (AC-II) is a cAMP-generating enzyme which, in the context of activation by Gsalpha, is further stimulated by protein kinase C or G protein betagamma subunits. Using in situ hybridization we have found a biphasic variation in AC-II mRNA within the rat SCN during the light-dark cycle (peaks at Zeitgeber time 6 and 18) and also in constant darkness (peaks at circadian time 2 and 14). The cingulate cortex showed no such variation. These findings suggest that circadian changes in AC-II expression may be pertinent to the rhythmic functions of the SCN.
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PMID:Circadian changes of type II adenylyl cyclase mRNA in the rat suprachiasmatic nuclei. 981 69

Despite the demonstration that chronic morphine increases phosphorylation of multiple substrate proteins, their identity has, for the most part, remained elusive. Thus far, chronic morphine has not been shown to increase the phosphorylation of any identified effector protein. This is the first demonstration that persistent activation of opioid receptors has profound effects on phosphorylation of adenylyl cyclase (AC). A dramatic increase in phosphorylation of AC (type II family) was observed in ileum longitudinal muscle myenteric plexus preparations obtained from chronic morphine-treated guinea pigs. Analogous results were obtained when AC was immunoprecipitated using two differentially directed AC antibodies. The magnitude of the augmented AC phosphorylation was substantially attenuated by chelerythrine, a protein kinase C-selective inhibitor. These results suggest the potential relevance of increased phosphorylation (protein kinase C-mediated) of AC to opioid tolerant/dependent mechanisms. Because phosphorylation of AC isoforms (type II family) can significantly increase their stimulatory responsiveness to Gsalpha and Gbetagamma, this mechanism could underlie, in part, the predominance of opioid AC stimulatory signaling observed in opioid tolerant/dependent tissue. Moreover, in light of the fact that many G protein-coupled receptors signal through common effector proteins, this effect provides a mechanism for divergent consequences of chronic morphine treatment and could explain the well documented complexity of changes that accompany the opioid tolerant/dependent state.
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PMID:Chronic morphine augments adenylyl cyclase phosphorylation: relevance to altered signaling during tolerance/dependence. 985 21

We have previously found that the D5 dopamine receptor couples to a G-protein other than Gsalpha, and could be involved in signaling pathways other than regulation of adenylyl cyclase. To describe interactions of the D5 receptor with cellular effectors, we used GH4C1 cells transfected with cDNA for the human D5 receptor. Thyrotropin-releasing hormone (TRH, 100 nM) stimulated accumulation of inositol phosphates (IPs) fivefold in D5GH4C1 cells. Dopamine (DA, 10 microM) inhibited TRH-stimulated IP values by 29%; at higher concentrations (100 microM), maximal inhibition of 61% was observed. The D5 agonist SKF R-38393 (10 microM) mimicked this effect (28% inhibition). SCH 23390, a D5 antagonist, blocked the inhibition caused by both DA and SKF R-38393. Spiperone, a D2 receptor antagonist, did not block the inhibition. The D2 agonist (+/-)-2-(N-phenylethyl-N-propyl)amino-5-hydroxytetralin (PPHT) did not inhibit TRH-stimulated IP production, nor did it augment the effect of D5 agonists. The DA-mediated suppression of IP levels was not sensitive to pertussis toxin; cholera toxin blocked both TRH stimulation and DA suppression of IP accumulation in response to 100 nM TRH. Neither dibutyryl cAMP nor forskolin lowered IP formation in response to TRH. Phorbol ester decreased TRH-stimulated IP accumulation in D5GH4C1 cells; however, an inhibitor of protein kinase C (PKC) did not block the effect of DA.
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PMID:Inhibition of hormonally induced inositol trisphosphate production in Transfected GH4</ sup>C1 cells: A novel role for the D5 subtype of the dopamine receptor. 1008 53

Cholera toxin covalently ADP-ribosylates the a subunit of Gs proteins. The modified Gsalpha activates adenylate cyclase and leads to a dramatic increase in intracellular cAMP. The effect of cholera toxin on the production of tumor necrosis factor (TNF-alpha), a critical mediator of toxicity for a number of bacterial and viral infections, has not been examined. Here we show that cholera toxin stimulated human monocytes to secrete TNF-alpha. The subunit A of cholera toxin alone also induced TNF-alpha production, suggesting that TNF-alpha production is mediated through ADP-ribosylation activity of the toxin. Inhibitors of ADP-ribosylation such as 3-aminobenzamide and niacinamide blocked TNF-alpha induction. However, cyclic AMP analogs and adenylate cyclase activator forskolin did not induce TNF-alpha production in monocytes, suggesting that TNF-alpha induction is independent of cAMP. Furthermore, cholera toxin-induced TNF-alpha production was suppressed by protein kinase C inhibitors H7 and sphingosine and by phospholipase C inhibitors U73122 and ET-18-OCH3, suggesting that PLC and PKC mediate TNF-alpha induction. Cholera toxin-mediated induction of TNF-alpha occurs at the transcription level as demonstrated by the time-dependent expression of TNF-alpha mRNA. These results raise the possibility that TNF-alpha may play an important role in cholera toxin-mediated toxicity and demonstrate that cholera toxin activates TNF-alpha production through PLC-dependent and cAMP-independent pathways. The probable mechanisms of signal transduction from cholera toxin to PLC in monocytes will be discussed.
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PMID:Cholera toxin induces tumor necrosis factor alpha production in human monocytes. 1054 36


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