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)

Single, large-conductance chloride-selective channels were studied in the membrane of pig aortic endothelial cells. These channels were usually inactive in cell-attached recordings and activated spontaneously upon formation of inside-out patches or amphotericin B-perforated vesicles. Channel activity was voltage dependent, with a maximum open probability within the range of -20 mV to + 20 mV. Addition of 1 mM Zn2+ to either the cytoplasmic or extracellular side blocked channel activity reversibly. Extracellular 4,4'-diisothiocyanostilbene-2,2'-disulphonic acid (DIDS) blocked the channels; the concentration necessary for half-maximum blockade was 100 mumol/l. The frequency of observing channels in cell-attached patches increased from less than 5% to 27% when cells were treated for several minutes with 1 mumol/l bradykinin and to 80% in the presence of the calcium ionophore A23187 (1 mumol/l). Both agents increase the cytoplasmic Ca2+ concentration, thereby stimulating nitric oxide (NO) synthesis and cGMP formation in endothelial cells. Sodium nitroprusside (100 mumol/l), which spontaneously releases NO, did not increase Cl- channel activity in intact cells. Polymyxin B (100 mumol/l), an inhibitor of protein kinase C, clearly enhanced Cl- channel activity in intact cells, resulting in the observation of Cl- channels in 70% of cell-attached patches. Our results demonstrate the existence of a large-conductance (LC-type) Cl- channel in vascular endothelium which is subject to a complex cellular regulation, possibly involving inhibition via phosphorylation by protein kinase C, and activation by a Ca2(+)-dependent process which is different from the NO/cGMP pathway.
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PMID:Voltage-sensitive chloride channels of large conductance in the membrane of pig aortic endothelial cells. 138 65

Thrombin, the key regulatory protein of hemostasis, is a potent stimulus for endothelial cell activation, a process implicated in a variety of ischemic, thrombotic, and inflammatory vascular disorders. Activation of the thrombin receptor requires a novel mechanism of receptor proteolysis generating a tethered receptor ligand. Synthetic peptides whose sequences are identical to this newly exposed receptor NH2-terminus reproduce thrombin effects on human and bovine endothelial cell activation. Receptor cleavage by catalytically active alpha-thrombin is tightly coupled to a PI-PLC, with resultant generation of IP3 and DAG, increases in [Ca2+]i, and translocation of PKC (Fig. 3). Both the increase in [Ca2+]i and PKC activation are required for thrombin-stimulated PLA2 and PLD activity, PGI2 synthesis, and barrier dysfunction, the latter occurring as the result of Ca2+ and PKC effects on specific cytoskeletal protein elements and other contractile proteins (Fig. 3). Further investigations are ongoing to identify more clearly not only the precise biochemical intermediates involved in the endothelial cell response to thrombin but also the specific protein kinase systems involved in thrombin-mediated signal transduction in vascular endothelium.
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PMID:Molecular mechanisms of thrombin-induced human and bovine endothelial cell activation. 140 26

Thrombin, the key regulatory protein of hemostasis, has been implicated in a variety of important endothelial cell processes closely linked to endothelial signal transduction mechanisms. An initial event, following receptor binding by catalytically active alpha-thrombin, appears to be the activation of a G-protein-coupled, PI-specific PLC, with resultant generation of IP3 and DAG, with increases in [Ca2+]i, and activation and translocation of PKC (Fig. 9). PKC activation results in down-regulation of PLC, as demonstrated by inhibition of agonist-induced increases in [Ca2+]i, whereas PLA2 activity is up-regulated, with a resultant increase in endothelial PGI2 synthesis. Recently, we have demonstrated that activity of membrane-bound, endothelial PLD, is also up-regulated by PKC activation. In addition to its modulatory role in endothelial cell phospholipase activities, PKC activation appears to play a critical role in thrombin-mediated endothelial barrier dysfunction, likely via specific cytoskeletal protein phosphorylation. A temporal relationship between alpha-thrombin-mediated signal transduction and specific cellular responses, such as PGI2 synthesis and barrier dysfunction, can be established (Fig. 2). Further investigations are ongoing to identify more clearly the precise biochemical intermediates involved in the endothelial cell response to thrombin, as well as the role of differential phosphorylation by various protein kinase systems in thrombin-mediated signal transduction in vascular endothelium.
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PMID:The role of protein kinase C in alpha-thrombin-mediated endothelial cell activation. 157 13

The influence of melatonin on alpha- and beta-adrenergic responses of vascular smooth muscle ex vivo were examined in these experiments. Melatonin caused a dose-dependent relaxation of precontracted (30 mM KCl) vascular smooth muscle. This response was not affected by the removal of vascular endothelium. Melatonin (10 nM) reduced the efficacy, but not potency, of the contractile responses to methoxamine and clonidine. Melatonin had no effect on the vascular beta-adrenergic response to isoproterenol. Pretreatment of vascular rings with lithium sulfate (0.1 mM) completely blocked the relaxation in response to melatonin, suggesting that the inositol phosphate pathway may be involved in this relaxation. Furthermore, pretreatment of vascular rings with phorbol 12-myristate-13-acetate, an activator of protein kinase C, antagonized the relaxation response to melatonin. Pharmacologic doses of melatonin (0.1 mM) slightly impaired the vascular smooth muscle response to calcium. These data indicate that melatonin per se is capable of relaxing vascular smooth muscle and that low doses of melatonin impair alpha-1 and alpha-2 adrenergic responses without changes in the beta adrenergic response of vascular smooth muscle.
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PMID:Melatonin-induced relaxation of rat aorta: interaction with adrenergic agonists. 168 39

Stimulation of quiescent cultured fibroblasts with a variety of growth-promoting factors induces release of diacylglycerol (DG) and subsequent activation of protein kinase C (pkC), but the role of pkC in the induction of DNA synthesis and cell proliferation remains unclear. We have investigated the involvement of pkC in the response of Rat-1 fibroblasts to the newly described peptide endothelin-1 (Et-1), an agonist that is secreted by the vascular endothelium and that may play a role in the proliferative response of cells in the vessel wall. Addition of Et-1 to serum-deprived Rat-1 cells promoted DNA synthesis in the absence of additional factors and stimulated anchorage-independent growth in the presence of epidermal growth factor (EGF), indicating that Et-1 has many of the characteristics of a mitogen. The ability of Et-1 to stimulate both DNA synthesis and anchorage-independent growth was markedly reduced by the depletion of cellular pkC activity induced by prolonged exposure to 12-O-tetradecanoylphorbol-13-acetate (TPA). In contrast, the ability of Et-1 to induce both second messenger production and transcription of c-fos and c-jun was largely independent of cellular pkC activity. Production of DG in response to Et-1 persisted for greater than 12 h and may account for the ability of Et-1 to augment the G1-S phase transition. Although these observations indicate that functional pkC is not an essential component of the proximal pathway leading to rapid changes in gene transcription and second messenger production in response to Et-1 treatment, the data suggest that activation of pkC is an essential component of the downstream events responsible for the stimulation of cell proliferation and anchorage-independent growth in Rat-1 cells exposed to Et-1.
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PMID:Endothelin-1 stimulates DNA synthesis and anchorage-independent growth of Rat-1 fibroblasts through a protein kinase C-dependent mechanism. 212 23

Kaposi sarcoma is a common, though not inevitable consequence of AIDS. There is a body of opinion that believes that this sarcoma is derived from lymphatic endothelium, or at least from a failure of vascular endothelium to distinguish between whether it is attempting to be a blood vessel or a lymphatic. While immunodeficiency and its consequences have proved to be the most significant area of research, the general biology of endothelium, and especially angiogenesis, has perhaps been neglected. I predict that the most important new concept in the biology of endothelium is the recognition of mechanico-receptors as a determinant of its behavior. The concept is illustrated by articles from Oxford (Ryan 1989), from Boston, Massachusetts (Ingber & Folkman 1989), and from Moscow (Shirinsky et al 1989). Most authors studying endothelium have concentrated on blood vascular endothelium and ignored the rich lymphatic bed. Since the lymphatic is par excellence a mechanical receptor, this is perhaps surprising. The lymphatic functions by its responsiveness to mechanical forces, it is a fine control for hydrostatic pressure within the interstitium, and morphologically, its flat and attenuated endothelium linked to strong anchoring fibers is biologically exactly the kind of behavior required of a cell that is responsive to mechanical factors. Perhaps the best known mechanical receptor is the stretch receptor in the muscle fiber. The linkage of this receptor to the enzyme protein kinase C has been described. Ryan has also pointed out that protein kinase C may be an important mechanico-receptor in the fibroblast and possibly also universally in all cells, including lymphatic endothelium.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Grip and stick and the lymphatics. 221 67

Ca2+-mobilizing receptor-induced inositol phospholipid hydrolysis has been studied in cultured endothelial cells (EC) from human aorta, pulmonary artery, and umbilical vein. It was shown that in EC the release of inositol phosphates can be stimulated by histamine, thrombin, serotonin, acetylcholine, carbachol, bradykinin, vasopressin, angiotensin II, platelet-activating factor (PAF), the thromboxane A2 mimetic, U46619, and prostaglandin E2. The most effective agonists were thrombin, histamine, and PAF, producing two- to five-fold increases in inositol phosphate level, and a 50-90% elevation of the level of inositol trisphosphate within 5 min. Effects of other agonists were smaller, although significant. Incubation of EC with histamine or PAF for 1 h resulted in a four- to eight-fold decrease of beta-adrenoreceptor density in the plasma membranes. The activity of isoproterenol-stimulated adenylate cyclase was depressed, and the degree of stimulation by isoproterenol was reduced. Similar effects were obtained after treatment of EC with the protein kinase C activator 4 beta-phorbol 12 beta-myristate 13 alpha-acetate, suggesting a role of protein kinase C in receptor desensitization. It is concluded, that stimulation of inositol phospholipid hydrolysis, and, consequently, activation of protein kinase can cause receptor imbalance in human vascular endothelium. This mechanism may play a pivotal role in the pathogenesis of cardiovascular and pulmonary diseases.
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PMID:Regulation of phosphoinositide turnover in endothelium from human pulmonary artery, aorta and umbilical vein. Antagonistic action on the beta-adrenoceptor coupled adenylate cyclase system. 254 21

We have investigated the protein phosphorylation systems present in cultured bovine aortic and pulmonary artery endothelial cells. The cells contain cyclic AMP-dependent protein kinase, three calcium/calmodulin-dependent protein kinases, protein kinase C, and at least one tyrosine kinase. No cyclic GMP-dependent protein kinase activity was found. The cells also contained numerous substrates for cyclic AMP-dependent protein kinase and protein kinase C. Fewer substrates were found for the calcium/calmodulin-dependent protein kinases. There was little difference between either protein kinase activities or substrates when pulmonary artery endothelium was compared to aortic endothelium grown under similar culture conditions. It is likely that these various protein kinases and their respective substrate proteins are involved in mediating several of the actions of the hormones and drugs which affect the vascular endothelium.
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PMID:Protein phosphorylation in cultured endothelial cells. 374 80

Neutral endopeptidase 24.11, a membrane-bound metallopeptidase, cleaves, and degrades vasoactive peptides such as atrial natriuretic peptide, endothelin, angiotensin I, substance P, and bradykinin. Therefore, the presence of this metallopeptidase may contribute to the regulation of vascular tone and local inflammatory responses in the vascular endothelium and elsewhere. We determined neutral endopeptidase in cultured human endothelial cells from different vascular beds and studied its regulation by protein kinase C. Neutral endopeptidase was detected in all cultured endothelial cell types. Lowest concentrations were measured in human endothelial cells from umbilical veins (360 +/- 14 pg/mg protein), followed by pulmonary and coronary arteries; higher concentrations were found in endothelial cells from the cardiac microcirculation (1099 +/- 73 pg/mg protein). Neutral endopeptidase content increased during cell growth but was not affected by endothelial cell growth factor or modifications of the growth medium. Stimulation of protein kinase C with 1-oleoyl-2-acetyl-rac-glycerol (0.1 to 1 mumol/L) and phorbol 12-myristate 13-acetate (0.01 to 0.1 mumol/L) induced a time- and concentration-dependent increase of endothelial cells that was inhibited by cycloheximide (5 mumol/L), an inhibitor of protein synthesis. Incubation with phospholipase C (1 mumol/L) and thrombin (10 IU/mL) induced upregulation of neutral endopeptidase, resulting in 158 +/- 26% and 150 +/- 22% increases, respectively, compared with controls. The thrombin effect was inhibited by calphostin C (1 mumol/L), an inhibitor of protein kinase C. Endothelial neutral endopeptidase is constitutively expressed in endothelial cells from different origins and is inducible by thrombin via activation of the protein kinase C pathway.
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PMID:Regulation and differential expression of neutral endopeptidase 24.11 in human endothelial cells. 763 30

We examined the regulatory influence of nitric oxide on development of calcium- and protein kinase C-dependent basal tone in rings of thoracic aortas from rats with aortic coarctation-induced hypertension and from normotensive controls. Aortic rings from hypertensive rats but not those from normotensive rats, bathed in Krebs' bicarbonate buffer and subjected to 2 g of passive stretch, were relaxed by removal of calcium from the buffer and by the protein kinase C inhibitors staurosporine and calphostin C. Protein kinase C activity was much greater in homogenates of aortae from hypertensive rats than in those from normotensive controls (2124 +/- 785 versus 608 +/- 73 pmol.min-1.mg protein-1, respectively). Relaxant responses to removal of calcium and to staurosporine were greater in aortic rings rubbed to remove the vascular endothelium than in endothelium-intact rings (-1.07 +/- 0.12 versus -0.70 +/- 0.10 g tension/mg tissue, respectively, for calcium removal and -1.10 +/- 0.12 versus -0.65 +/- 0.08 g tension/mg tissue, respectively, for staurosporine). Treatment with an inhibitor of nitric oxide synthesis increased calcium-dependent tone in both intact and endothelium-denuded aortic rings from hypertensive rats. Conversely, the administration of sodium nitroprusside or L-arginine reversed tone in both intact and denuded aortic rings from hypertensive rats, but acetylcholine reversed tone only in intact rings. The relaxant effects of these agents were paralleled by increases in cyclic guanosine monophosphate in aortic tissue. We conclude that aortic rings from rats with aortic coarctation-induced hypertension display calcium-dependent, protein kinase C-mediated tone in the absence of exogenous vasoconstrictors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Calcium- and protein kinase C-dependent basal tone in the aorta of hypertensive rats. 772 28


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