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)

Human neutrophils respond to chemoattractants, resulting in their accumulation at an inflammatory site. Chemoattractants such as the C5a peptide, derived from the C5 complement factor, bind to inhibitory guanine nucleotide binding protein (Gi)-coupled seven membrane-spanning receptors expressed in neutrophils. C5a receptor activation results in the Gi-dependent activation of the mitogen-activated protein (MAP) kinase pathway in human neutrophils. C5a receptor ligation activates both B-Raf and Raf-1, with B-Raf activation overlapping but temporally distinct from that of Raf-1. B-Raf and Raf-1 both efficiently phosphorylate MAP kinase kinase (MEK-1). C5a also stimulates guanine nucleotide exchange and activation of Ras. Ras and Raf activation in response to C5a involves protein kinase C-dependent and -independent pathways. Activation of both Raf-1 and B-Raf was inhibited by protein kinase A stimulation, consistent with the inhibitory effects of increased cAMP levels on neutrophil function. The findings define a functional signal transduction pathway linking the neutrophil C5a chemoattractant receptor to the regulation of Ras, B-Raf, Raf-1, and MAP kinase.
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PMID:Mapping of the C5a receptor signal transduction network in human neutrophils. 809 Jul 90

The cytokine-mediated stimulation of sphingomyelin (SM) metabolism is emerging as an important signal transduction pathway via the generation of ceramide and sphingosine, products which have been shown to affect a wide variety of biological processes. Because SM-mediated signal transduction is initiated via the hydrolysis of an integral membrane phospholipid by a phospholipase C-like enzyme (sphingomyelinase) to yield lipids which modulate protein kinase C activity, the SM and phosphatidylinositol (PI) signaling pathways share certain similarities. The present study was undertaken to examine the potential for interplay between SM and PI turnover by testing the effects of sphingosine, sphingosine-1-phosphate, and ceramide on PI turnover. In dermal fibroblasts, sphingosine stimulated a rapid dose-dependent hydrolysis of PI, yielding inositol 1,4,5-triphosphate, followed by increased levels of intracellular calcium. Sphingosine-induced inositol phosphate (IP) accumulation was observed between 5 and 30 microM sphingosine with a maximal accumulation of 2.7-fold over control levels. Enhanced IP formation was measured as early as 5 s following sphingosine treatment and IP levels remained elevated for more than 60 min. Intracellular calcium mobilization accompanied the dose-dependent accumulation of IPs in response to sphingosine, although this effect was not apparent until after a 30-40-s lag period. Interestingly, sphingosine-1-phosphate stimulated a more rapid release of intracellular Ca2+ than sphingosine, but it had no effect on PI turnover. DL-threo-Dihydrosphingosine, a competitive inhibitor of sphingosine kinase, stimulates both PI turnover and Ca2+ flux, but does not block the action of sphingosine relative to those two processes. Ceramide (added as C2-ceramide), N-stearylamine, and stearoyl-D-sphingosine did not affect PI turnover or Ca2+ mobilization. Pretreatment of intact cells with pertussis toxin partially inhibited sphingosine-mediated IP accumulation, suggesting a role for guanine nucleotide binding protein(s) (G protein) in sphingosine-stimulated PI turnover. Furthermore, guanosine 5'-O-(3-thiotriphosphate) stimulated, whereas guanosine 5'-O-(2-thiodiphosphate) inhibited, sphingosine-induced IP accumulation in permeabilized cells. Collectively, these data suggest that sphingosine enhances PI turnover by stimulating phospholipase C activity, and the activation of this process may be modulated by G protein interactions. Thus, the regulation of PI turnover and Ca2+ mobilization by sphingosine may represent another mechanism by which sphingosine modulates cell function and that these effects can be distinguished from those of ceramide.
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PMID:Sphingosine-mediated phosphatidylinositol metabolism and calcium mobilization. 811 27

Serotonin (5-HT) potently contracts the fundus of the rat stomach; however, the associated transduction pathway has not been described fully. Experiments were performed in an attempt to gain insight into the coupling mechanism associated with this fundal 5-HT receptor. 5-HT-stimulated [35S]GTP gamma S binding to a protein which was recognized by anti-G alpha Z antiserum in a Mg(++)-dependent fashion. 5-HT increased [35S]GTP gamma S binding in the fundus, but not in the corpus of the rat stomach. 5-HT also enhanced the binding of [alpha-32P]GTP to the fundal protein and increased the hydrolysis of GTP to GDP in fundal membranes. The fundal protein which binds GTP is 25 to 29 kDa in size whereas the brain G alpha Z protein which is recognized by the anti-G alpha Z antibody is a 41 kDa protein. Mixing experiments revealed that the fundal guanine nucleotide binding protein does not appear to be a proteolytic product of the 41 kDa G alpha Z protein. Activating protein kinase C with phorbol-12-myristate, 13-acetate induced a concentration-dependent, noncompetitive inhibition of [35S]GTP gamma S binding to the fundal protein, and of 5-HT-induced contraction of fundal strips. Phorbol-12-myristate, 13-acetate did not alter carbachol- or KCl-mediated fundus contraction. Furthermore, the activation of [35S]GTP gamma S binding by serotonergic agonists and its inhibition by pharmacological antagonists corresponded to the known actions of these agents on contraction of fundal muscle. The results provide evidence that the 5-HT receptor in the rat stomach fundus is coupled directly or indirectly to a G alpha z-like protein which may mediate 5-HT-induced contraction in this tissue.
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PMID:Serotonin-induced muscle contraction in rat stomach fundus is mediated by a G alpha z-like guanine nucleotide binding protein. 824 27

Guanosine 5'-O-(thiotriphosphate) (GTP gamma S), an activator of guanine nucleotide binding protein (G protein), increased prostaglandin E2 (PGE2) production in saponin permeabilized rat thymic epithelial cells, TEA3A1. Aluminum fluoride (A1F4-), a cell permeable G protein activator, also stimulated PGE2 production and arachidonic acid (AA) release from TEA3A1 cells. Using A1F4- instead of GTP gamma S as a G-protein activator, we have investigated the mechanism of G-protein mediated stimulation of PGE2 production in TEA3A1 cells. Results from our experiments indicate that G protein mediated activation of AA metabolism in TEA3A1 cells is regulated by two independent mechanisms. One is by the stimulation of AA release via the activation of PLA2 enzymatic activity through PLC and PKC mediated pathway and the other is by a concomitant inhibition of AA incorporation into membrane phospholipids.
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PMID:Guanine nucleotide-binding protein stimulates arachidonic acid metabolism in TEA3A1 thymic epithelial cells by stimulating release and inhibiting incorporation of arachidonic acid. 829 92

Studies were performed to identify the site at which activation of protein kinase C (PKC) inhibits arginine vasopressin (AVP)-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) accumulation in cultured rat inner medullary collecting tubule (RIMCT) cells. Neither endogenous stimulation of PKC by epidermal growth factor (EGF) nor the addition of exogenous 1,2-dioctanoyl-sn-glycerol (DOG) impaired forskolin-stimulated cAMP accumulation. Similarly, neither EGF nor DOG altered cAMP generation in response to cholera toxin. However, pretreatment of RIMCT cells with pertussis toxin resulted in loss of inhibition of AVP-stimulated cAMP accumulation by DOG. Likewise, the ability of the phorbol ester, phorbol 12-myristate 13-acetate (PMA), to inhibit AVP-stimulated cAMP accumulation was eliminated by pretreatment with pertussis toxin. PMA also inhibited AVP-stimulated adenylyl cyclase activity in plasma membranes prepared from rat inner medullas. In contrast to its effects on AVP, activation of PKC did not impair cAMP accumulation in response to isoproterenol or prostaglandin E2. These studies demonstrate that PKC-mediated inhibition of AVP-stimulated cAMP accumulation in cultured RIMCT cells requires the intact inhibitory guanine nucleotide binding protein Gi.
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PMID:Protein kinase C inhibits arginine vasopressin-stimulated cAMP accumulation via a Gi-dependent mechanism. 838 49

1. We have previously demonstrated that M2 and M3 muscarinic receptors coexist in the circular smooth muscle of canine proximal colon. Activation of receptors of the M2 subtype leads to inhibition of adenylyl cyclase activity through the GTP-binding protein, Gi, while M3 receptors are coupled to a pertussis toxin-insensitive GTP-binding protein and mediate phosphoinositide hydrolysis. 2. In the present study, the interactions between these second messenger systems were examined. Activation of either protein kinase C or adenosine 3':5'-cyclic monophosphate (cyclic AMP)-dependent protein kinase attenuated carbachol-stimulated phosphoinositide hydrolysis without affecting basal activity. Activation of both protein kinases produced greater attenuation of inositol 1,4,5-trisphosphate formation than activation of either kinase alone. 3. In contrast to its inhibitory effect on phosphoinositide hydrolysis, activation of protein kinase C had no effect on adenylyl cyclase activity. 4. Activation of protein kinase C by phorbol ester treatment resulted in the sequestration of M3 muscarinic receptors from the cell surface without effecting the M2 muscarinic receptor population. Sequestered M3 muscarinic receptors were not rapidly degraded. 5. In contrast, elevation of cellular cyclic AMP decreased the affinity of cell surface muscarinic receptors for an antagonist radioligand without affecting their density. 6. Muscarinic agonist binding was not affected by either activation of protein kinase C or elevation of cellular cyclic AMP. 7. These data support the notion of negative feedback by protein kinase C and cyclic AMP-dependent protein kinase on phosphoinositide hydrolysis. In canine colonic circular smooth muscle this negative feedback regulation of inositol phosphate generation by muscarinic receptor stimulation does not appear to involve the guanine nucleotide binding protein:receptor interaction.
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PMID:Protein kinase regulation of muscarinic receptor signalling in colonic smooth muscle. 838 29

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

Opioids relieve painful stimuli by interacting with the opioid receptor subtypes, mu, delta, and kappa, in brain regions and spinal cord. Tolerance reduces medication effectiveness and causes a right-hand shift in the dose-response curve. The mechanisms involved in the development of opioid tolerance remain not clear. Following long-term opioid treatment, either a decrease or increase in opioid receptors was demonstrated, depending on the types or subtypes of receptors and the central areas to which they are distributed. Opioid receptors, like most other hormone and neurotransmitter receptors, have been shown to mediate their effects through guanine nucleotide binding protein (G protein). Studies regarding chronic treatment with opioid agonists suggest that the uncoupling of the opioid receptors from their corresponding G protein may play an important role in opioid tolerance. The NMDA (N-methyl-D-aspartate) receptors have also been demonstrated involving not only in nociception and pain processing but also in the development of opioid tolerance. The sustained potentiation of NMDA receptor-mediated responses may be provided through activation of PKC (protein kinase C). Furthermore, NMDA receptor-mediated intracellular translocation and activation of PKC may be a critical step in the development of opioid tolerance. The NMDA receptors can also induce the synthesis of NO (nitric oxide) through the activation of NOS (NO synthase). NOS inhibitors were also shown to prevent the development of opioid tolerance, therefore, NO was suggested to play a role in opioid tolerance development. Although much evidence indicates the reasons of opioid tolerance, it is still worth further investigation to explore the mechanisms of multiplicity of opioid receptors and complexity of intracellular biochemical events.
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PMID:[Cellular mechanism of opioid tolerance]. 908 51

1. The action of GTP-binding proteins on ATP-sensitive potassium (KATP) channels was investigated. KATP channels were expressed in a mammalian cell line (COS-1 cells) by cotransfecting vectors carrying the sulphonylurea receptor (SUR1) and BIR (Kir6.2), a member of the inward rectifier K+ channel family. G proteins were also tested on KATP channels composed of an isoform of SUR1, SUR2A, in combination with Kir6.2. 2. The alpha and beta gamma subunits of the GTP binding protein G1 were tested separately in inside-out patches under continuous recording. G alpha-11 increases the activity of SUR1-Kir6.2 and SUR2A-Kir6.2 channels by 200 and by 30%, respectively. 3. G alpha-12 does not increase the activity of SUR1-Kir6.2 channels, but increase the activity of SUR2A-Kir6.2 channels by 30%. 4. Control experiments showed that GTP gamma S, a specific activator of G proteins, and heat-inactivated G alpha-11 do not increase the single channel activity. 5. No effects of the other subunits (beta gamma) from either G11 or G12 on the single channel activity were observed. 6. The protein kinase C inhibitors H7 and an inhibitory peptide (FARKGALRQKNV) had no effect on the modulatory action of G alpha-11 on SUR1-Kir6.2 channels. 7. We conclude that both types of reconstituted KATP channels are modulated by G proteins.
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PMID:Modulation of reconstituted ATP-sensitive K(+)-channels by GTP-binding proteins in a mammalian cell line. 951 95

Previous work from our laboratory demonstrated that 1,25(OH)2D3 rapidly stimulated hydrolysis of membrane polyphosphoinositides (PI) in rat colonocytes and in Caco-2 cells, generating the second messengers DAG and IP3. [Ca2+]i subsequently increased due to IP3-mediated release of intracellular Ca2+ stores, and to Ca2+ influx through a receptor-mediated Ca channel. Studies examining purified antipodal plasma membranes and experiments using Caco-2 cell monolayers found that 1,25(OH)2D3 influenced PI turnover only in the basolateral (BLM) and not brush border (BBM) membranes. Vitamin D analogues with poor affinity for the vitamin D receptor were found to effectively stimulate PI turnover, suggesting the presence of a unique vitamin D receptor in the BLM. Studies from our laboratory have demonstrated saturable, reversible binding of 1,25(OH)2 D3 to colonocyte BLM. Recently, we found that 1,25(OH)2D3 activated the tyrosine kinase c-src in colonocyte BLM by a heterotrimeric guanine nucleotide binding protein (G-protein)-dependent mechanism, with subsequent phosphorylation, translocation to the BLM, and activation of PI-specific phospholipase C gamma. Due to the rise in [Ca2+]i and DAG, two isoforms of protein kinase C (PKCalpha and PKCbeta2), but not other isoforms were activated by 1,25(OH)2D3 in rat colonocytes. Recent studies demonstrated that the seco-steroid translocated the beta2 isoform to the BLM, but not the BBM. In contrast, the alpha isoform did not translocate to either antipodal plasma membrane, but modulated IP3-mediated Ca2+ release from the endoplasmic reticulum. Preliminary studies have shown that 1,25(OH)2D3 also activated phosphatidylcholine phospholipase D (PLD) in Caco-2 cells, generating phosphatidic acid and contributing to the sustained rise in DAG. PLD stimulation occurred by both PKC-dependent and -independent mechanisms. Inhibitors of G-proteins, c-src, and PKC blunted the seco-steroid-mediated activation of PLD. Cells stably transfected with sense PKCalpha showed increased 1,25(OH)2D3-stimulated PLD activation, whereas transfectants with antisense PKCalpha had an attenuated response. In addition, 1,25(OH)2D3 also regulated PLD by activating the monomeric G-protein rho A by a mechanism independent of the G-protein/ c-src/PKC pathway.
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PMID:Rapid effects of 1,25(OH)2 vitamin D3 on signal transduction systems in colonic cells. 1032 82


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