EC:2.7.11.13 - FACTA Search

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)

There is increasing evidence for rapid nongenomic effects of aldosterone. Aldosterone has been demonstrated to alter intracellular pH and calcium in isolated cells. However, few studies have correlated these effects with aldosterone-mediated physiological responses. Therefore, we studied rapid effects of aldosterone on vascular reactivity, intracellular Ca2+, and pH in resistance vessels. Furthermore, we explored whether the new antimineralocorticoid drug eplerenone could effectively block nongenomic aldosterone-mediated effects. The vasoconstrictor action of aldosterone was examined directly by determining the diameter of small resistance mesenteric vessels (160-200 microm resting diameter), simultaneously with intracellular pH or Ca2+. Aldosterone (10 nm) caused a rapid constriction of resistance vessels (8.1% +/- 1.0% reduction in the diameter below control conditions, P < 0.05). Aldosterone potentiated phenylephrine-mediated constriction in small and large mesenteric vessels. Aldosterone induced a rapid increase of intracellular Ca2+ and cellular alkalinization. Vasoconstrictor action of aldosterone and nongenomic effects on the sodium-proton exchanger (NHE1) activity or intracellular Ca2+ responses was abolished by eplerenone. The vasoconstrictor response of aldosterone was related to phosphatidylinositol 3-kinase (PI3-K): the hormone decreased protein kinase B phosphorylation; pharmacological inhibition of PI3-K (10 microm LY294002 or 1 microm wortmannin) increased arterial contractility. Inhibitors of ERK 1/2 phosphorylation (15 microm PD98059) had no effect on aldosterone-mediated vasoconstriction. Inhibition of protein kinase C with 1 microm bi-sindolylmaleimide I and/or inhibition of NHE1 with 100 microm amiloride abolished aldosterone vasoconstrictor action of resistance mesenteric arteries. We conclude that aldosterone-mediated increase in vascular tone is related to a nongenomic mechanism that involves protein kinase C, PI3-K, and NHE1 activity. Eplerenone is an effective blocker of nongenomic effects of aldosterone in vascular tissue.
...
PMID:Eplerenone blocks nongenomic effects of aldosterone on the Na+/H+ exchanger, intracellular Ca2+ levels, and vasoconstriction in mesenteric resistance vessels. 1571 38

The present study evaluated the effect of interferon-gamma (IFN-gamma) on intestinal Na+/H+ exchange (NHE) activity and the intracellular signaling pathways set into motion after IFN-gamma receptor activation. Caco-2 cells express endogenous NHE1, NHE2 and NHE3 proteins, as detected by immunoblotting. Short- (0.5 h) and long- (24 h) term exposure of Caco-2 cells to IFN-gamma resulted in a concentration-dependent decrease in NHE activity. Inhibition of NHE activity by IFN-gamma was absent in cariporide-treated cells, but not in cells treated with S-3226. The long-term exposure to IFN-gamma was accompanied by a 20% increase in surface NHE1 abundance and no changes in total NHE1 abundance. Inhibition of Raf1, mitogen-activated protein kinase kinase (MAPKK/MEK) and p38 MAPK with, respectively, GW 5074, PD 98059 and SB 203580 and downregulation of protein kinase C (PKC) with phorbol-12,13-dibutyrate (100 nM for 24 h) prevented inhibition of NHE activity by IFN-gamma (0.5 and 24 h exposure). The signal transducer and activator transcription factor 1 (STAT1) inhibitor epigallocatechin-3-gallate (EGCG) prevented inhibition of NHE activity by long- but not the short-term treatment with IFN-gamma. Treatment with IFN-gamma activated phospho-p38 MAPK, this effect being detected as early as 1 h, persisting over 3 h and decreasing after 24 h. IFN-gamma produced a sustained action of phospho-STAT1 that was prevented by EGCG and partially attenuated by SB 203580 and insensitive to downregulation of PKC. In conclusion, short- and long-term inhibition of NHE1 activity by IFN-gamma involves a complex signaling pathway that includes PKC activation and STAT1 phosphorylation, respectively, but is not accompanied by downregulation of NHE1.
...
PMID:Signaling of short- and long-term regulation of intestinal epithelial type 1 Na+/H+ exchanger by interferon-gamma. 1572 92

There is accumulating evidence that thyroid hormone metabolism is altered after myocardial infarction (AMI) but its physiological relevance remains largely unknown. The present study investigated the possible role of thyroid hormone signaling in the response of the post-infarcted heart to ischaemia-reperfusion. Wistar rats were subjected to left coronary artery ligation (AMI), or sham operation (SHAM). After 8 weeks, hearts from AMI and SHAM rats were perfused in Langendorff mode and subjected to 20 min of zero-flow global ischaemia (I) and 45 min of reperfusion (R); AMI(I/R), n = 7 and SHAM(I/R), n = 7. Basal left ventricular pressure (LVDP), +dp/dt, and -dp/dt were significantly reduced. Left ventricular weight of the viable myocardium was increased by 14% in the AMI as compared to SHAM hearts, P < 0.05. T(3) and T(4) plasma levels in nM were 1.83 (0.08) and 53.3 (2.9) for SHAM and 1.76 (0.06) and 59.4 (5.2) for AMI rats, respectively, P > 0.05. TRalpha1 and TRbeta1 expression levels were 1.3- and 1.8-fold less in AMI than in SHAM hearts, P < 0.05. Furthermore, SERCA and NHE1 expression levels were 2.1- and 1.8-fold less in AMI than in SHAM, P < 0.05. PKCepsilon was 1.35-fold more in AMI compared to SHAM, P < 0.05. Myocardial glycogen content (in micromol/g) was 7.8 (1.2) in AMI as compared to 4.4 (0.5) for SHAM hearts, P < 0.05. After I/R, left ventricular end-diastolic pressure at 45 min of R (LVEDP45 in mmHg) was 20.3 (3.2) for AMI(I/R) vs 50.6 (4.8) mmHg for SHAM(I/R), P < 0.05. LDH release per gram of tissue was 251 (103) for AMI(I/R) and 762 (74) for SHAM(I/R), P < 0.05. In conclusion, TRalpha1 and TRbeta1 are downregulated after myocardial infarction and this was associated with altered expression of thyroid hormone responsive genes and increased tolerance of the post-infarcted heart to ischaemia-reperfusion injury.
...
PMID:Thyroid hormone receptors alpha1 and beta1 are downregulated in the post-infarcted rat heart: consequences on the response to ischaemia-reperfusion. 1613 16

We studied pathways involved in the proliferation of rat C6 glioma cells induced by lysophosphatidic acid (LPA), a phospholipid with diverse biological functions. LPA induced a dose-responsive proliferation of C6 cells after 48 h. Proliferation was blocked by inhibitors of the sodium/proton exchanger type 1 (NHE1), Rho-associated kinase, the phosphatidylinositol 3-kinase/Akt pathway (PI3K/Akt), protein kinase C (PKC) and extracellular signal regulated kinase kinase (MEK). Phospho-specific antibodies were used to investigate the pathways involved. LPA induced transient (10 min) phosphorylations of ERK 1/2, Akt and the transcription factor CREB. The LPA-induced phosphorylation of ERK 1/2 and CREB was blocked by inhibition of PI3K, PKC and MEK, but that of Akt was only inhibited by wortmannin, the PI3K inhibitor. Inhibition of Rho kinase or NHE1 did not reduce the LPA-induced phosphorylation of ERK, Akt or CREB. The results were compared with the effects of LPA on transduction pathways in other cell types.
...
PMID:Signal transduction mechanisms involved in the proliferation of C6 glioma cells induced by lysophosphatidic acid. 1617 63

Targeting nanocarriers (NC) loaded by antioxidant enzymes (e.g., catalase) to endothelial cell adhesion molecules (CAM) alleviates oxidative stress in the pulmonary vasculature. However, antioxidant protection is transient, since CAM-targeted catalase is internalized, delivered to lysosomes, and degraded. To design means to modulate the metabolism and longevity of endothelial cell (EC)-targeted drugs, we identified and manipulated cellular elements controlling the uptake and intracellular trafficking of NC targeted to ICAM-1 (anti-ICAM/NC). BAPTA, thapsigargin, amiloride, and EIPA inhibited anti-ICAM/NC uptake by EC and actin rearrangements induced by anti-ICAM/NC (required for uptake), suggesting that member(s) of Na(+)/H(+) exchanger family proteins (NHE) regulate these processes. Consistent with this hypothesis, an siRNA specific for the plasmalemma NHE1, but not the endosome-associated NHE6, inhibited actin remodeling induced by anti-ICAM/NC and internalization. Anti-ICAM/NC binding to EC stimulated formation of a transient ICAM-1/NHE1 complex. One hour after uptake, ICAM-1 dissociated from NHE1, and anti-ICAM/NC were transported to NHE6-positive vesicles en route to lysosomes. Inhibition of PKC (an activator of intracellular NHE) accelerated nanocarrier lysosomal trafficking. In contrast, monensin, which enhances the endosomal sodium influx and proton efflux maintained by NHE6, inhibited delivery of anti-ICAM/NC to lysosomes by switching their trafficking to a plasma membrane recycling pathway. This markedly prolonged the protective effect of catalase-coated anti-ICAM/NC. Therefore, 1) NHE1 and NHE6 regulate distinct phases of anti-ICAM/NC uptake and trafficking; 2) pharmacological agents affecting these regulatory elements alter the itinerary of anti-ICAM/NC intracellular trafficking; and 3) these agents modulate duration of the therapeutic effects of targeted drugs.
...
PMID:Control of intracellular trafficking of ICAM-1-targeted nanocarriers by endothelial Na+/H+ exchanger proteins. 1660 94

Epidermal growth factor (EGF) is predominantly secreted by salivary glands and activates Na(+)/H(+) exchanger-1 (NHE-1), which regulates intracellular pH (pH(i)). We investigated the roles of EGF and NHE-1 in esophageal epithelial defense against acid using human esophageal epithelial cell lines and a rat chronic esophagitis model. Esophageal epithelial cells were incubated with acidified medium in the absence or presence of EGF. Cell viability and changes in pH(i) were measured. Chronic acid reflux esophagitis was induced in rats with and without sialoadenectomy. Esophageal lesion index, epithelial proliferation, and expression of EGF receptors and NHE-1 were examined. EGF protected esophageal epithelial cells against acid in a dose-dependent manner, and the cytoprotective effect of EGF was completely blocked by treatment with NHE-1 inhibitors. Tyrosine kinase, calmodulin, and PKC inhibitors significantly inhibited cytoprotection by EGF, whereas MEK, phosphatidylinositol 3-kinase, and PKA inhibitors had no effect. EGF significantly increased pH(i) recovery after NH(4)Cl pulse acidification, and this increase in pH(i) recovery was significantly blocked by inhibitors of calmodulin and PKC. Sialoadenectomy led to an increase in the severity of chronic esophagitis but affected neither epithelial proliferation nor expression of EGF receptors. Expression of NHE-1 mRNA was increased in esophagitis and upregulated in rats with sialoadenectomy. The increasing severity of esophagitis in rats with sialoadenectomy was prevented by exogenous administration of EGF. In conclusion, EGF protects esophageal epithelial cells against acid through NHE activation via Ca(2+)/calmodulin and the PKC pathway. Deficiency in endogenous EGF is associated with increased severity of esophagitis. EGF and NHE-1 play crucial roles in esophageal epithelial defense against acid.
...
PMID:Roles of epidermal growth factor and Na+/H+ exchanger-1 in esophageal epithelial defense against acid-induced injury. 1630 34

The ubiquitous Na+/H+ exchanger NHE1 is regulated by protein phosphorylation events, but the mechanisms involved are incompletely understood. We recently cloned NHE1 from the red blood cells of the winter flounder, Pleuronectes americanus (paNHE1), and demonstrated its activation by osmotic cell shrinkage, beta-adrenergic stimuli, and the Ser/Thr protein phosphatase PP1 and PP2A inhibitor calyculin A(CLA) (Pedersen et al. [2003] Am. J. Physiol. 284, C1561-C1576). Here, we investigate the mechanisms involved in paNHE1 activation by these stimuli. Osmotic shrinkage and CLA were only partially additive in their effects on paNHE1 activity, and CLA-mediated paNHE1 activation was inhibited by osmotic cell swelling. Activation by the beta-adrenergic agonist isoproterenol (IP) was fully additive to activation by osmotic shrinkage or CLA. IP-mediated, but neither shrinkage- nor CLA-mediated paNHE1 activation were associated with an increase in cellular cyclic adenosine monophosphate (cAMP) level. IP-mediated activation was partially blocked by the protein kinase A (PKA) inhibitor H89 (10 microM), whereas shrinkage- and CLA-mediated activation were unaffected. All three stimuli activated paNHE1 in a manner unaffected by inhibitors of protein kinase C (calphostin C, 5 microM) and protein kinase G (KT5823, 10 microM) as well as of myosin light chain kinase (ML-7, 10 microM). IP-mediated, but not shrinkage-mediated, paNHE1 activation was associated with an increase in serine phosphorylation of the paNHE1 protein. It is suggested that paNHE1 activation by osmotic shrinkage and by PP1/PP2A inhibition involves partially convergent signaling pathways, whereas activation of paNHE1 by beta-adrenergic stimuli is mediated by a separate pathway.
...
PMID:Regulation of the Pleuronectes americanus Na+/H+ exchanger by osmotic shrinkage, beta-adrenergic stimuli, and inhibition of Ser/Thr protein phosphatases. 1667 60

Cyclosporin A (CyA) causes renal Na(+) retention which may lead to arterial hypertension. The apical Na(+)/H(+) exchanger (NHE3) is responsible for bulk proximal tubular Na(+) reabsorption. The aim of this study was to investigate the effects of CyA on the NHE3 of polarized proximal tubular cells to evaluate cellular mechanisms of CyA-associated arterial hypertension. The change of the intracellular pH (Delta-[pH](i)/min) was determined as a measure of the activity of the NHE in LLC-PK(1)/PKE(20) cells using 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein (BCECF). The NHE activity was identified as the apical NHE3 since it could be inhibited by the inhibitor S3226, but not by inhibitors of the basolateral isoform (NHE1) amiloride or HOE 694. CyA stimulated the NHE3 activity dose dependently. The mean increase stimulated by relevant CyA concentrations was 61+/-11%. A 24-h application of CyA also stimulated an increase of NHE3 activity which did not seem to be mediated by an increase of NHE3 RNA expression. The less immunosuppressive derivatives cyclosporin H and cyclosporin G caused NHE3 activation as well. Carbachol and ATP, which both induce a Ca(2+) release from internal Ca(2+) stores, also increased the NHE3 activity. The Ca(2+) chelator 1,2-bis-(2-aminophenoxy)-ethane-N,N,-N',N'-tetraacetic acid tetraacetoxymethyl ester (BAPTA-AM) abolished the CyA-associated NHE3 stimulation, whereas low extracellular Ca(2+) had no effect. CyA-associated effects did not seem to be mediated via inhibition of protein kinase C (PKC). CyA had no additive effects on the angiotensin II-associated NHE3 stimulation. Concurrent application of losartan did not impair the CyA-induced NHE3 stimulation. In conclusion CyA stimulates the apical NHE3 in proximal tubular cells. This is mediated by Ca(2+) release from intracellular stores but is independent of the action of angiotensin II or PKC.
...
PMID:Cyclosporin A stimulates apical Na+/H+ exchange in LLC-PK1/PKE20 proximal tubular cells. 1677 4

In cardiac myocytes, sustained (3 min) intracellular acidosis activates the ERK1/2 (extracellular-signal-regulated kinase 1/2) pathway and, through this pathway, increases sarcolemmal NHE (Na+/H+ exchanger) activity [Haworth, McCann, Snabaitis, Roberts and Avkiran (2003) J. Biol. Chem. 278, 31676-31684]. In the present study, we aimed to determine the time-dependence, pH-dependence and upstream signalling mechanisms of acidosis-induced ERK1/2 activation in ARVM (adult rat ventricular myocytes). Cultured ARVM were subjected to intracellular acidosis for up to 20 min by exposure to NH4Cl, followed by washout with a bicarbonate-free Tyrode solution containing the NHE1 inhibitor cariporide. After the desired duration of intracellular acidosis, the phosphorylation status of ERK1/2 and its downstream effector p90(RSK) (90 kDa ribosomal S6 kinase) were determined by Western blotting. This revealed a time-dependent transient phosphorylation of both ERK1/2 and p90(RSK) by intracellular acidosis (intracellular pH approximately 6.6), with maximum activation occurring at 3 min and a return to basal levels by 20 min. When the degree of intracellular acidosis was varied from approximately 6.8 to approximately 6.5, maximum ERK1/2 phosphorylation was observed at an intracellular pH of 6.64. Inhibition of MEK1/2 [MAPK (mitogen-activated protein kinase)/ERK kinase 1/2) by pre-treatment of ARVM with U0126 or adenoviral expression of dominant-negative D208A-MEK1 protein prevented the phosphorylation of ERK1/2 by sustained intracellular acidosis, as did inhibition of Raf-1 with GW 5074 or ZM 336372. Interference with Ras signalling by the adenoviral expression of dominant-negative N17-Ras protein or with FPT III (farnesyl protein transferase inhibitor III) also prevented acidosis-induced ERK1/2 phosphorylation, whereas inhibiting G-protein signalling [by adenoviral expression of RGS4 or Lsc, the RGS domain of p115 RhoGEF (guanine nucleotide-exchange factor)] or protein kinase C (with bisindolylmaleimide I) had no effect. Our data show that, in ARVM, sustained intracellular acidosis activates ERK1/2 through proximal activation of the classical Ras/Raf/MEK pathway.
...
PMID:Ras triggers acidosis-induced activation of the extracellular-signal-regulated kinase pathway in cardiac myocytes. 1683 Nov 26

In trout hepatocytes, hypertonicity and cytosolic acidification are known to stimulate Na+/H+ exchanger (NHE) activity, which contributes to recovery of cell volume and intracellular pH (pHi), respectively. The present study investigated the signalling mechanisms underlying NHE activation under these conditions. Exposing trout hepatocytes to cariporide, a specific inhibitor of NHE-1, decreased baseline pHi, completely blocked the hypertonicity-induced increase of pHi and reduced the hypertonicity-induced proton secretion by 80%. Changing extracellular pH (pHe) above and below normal values, and allowing cells to adjust pHi accordingly, significantly delayed alkalinization during hypertonic exposure, whereas following an acid load an enhanced pHi recovery with increasing pHe was seen. Chelating Ca2+, and thereby preventing the hypertonicity-induced increase in intracellular Ca2+ ([Ca2+]i), significantly diminished hypertonic elevation of pHi, indicating that Ca2+ signalling might be involved in NHE activation. A reduction in alkalinization and proton secretion was also observed in the presence of the protein kinase A (PKA) inhibitor H-89 or the calmodulin (CaM) inhibitor calmidazolium. A complete inhibition of hypertonic- and acidification-induced changes of pHi concurrent with an increase in hypertonically induced proton efflux was seen with the protein kinase C (PKC) inhibitor chelerythrine. Recovery of pHi following sodium propionate addition was reduced by more than 60% in the presence of cariporide, was sensitive to PKA inhibition, and tended to be reduced by CaM inhibition. In conclusion, we showed that NHE-1 is the main acid secretion mechanism during hypertonicity and recovery following acid loading. In addition, Ca2+-, PKA- and CaM-dependent pathways are involved in NHE-1 activation for recovery of cell volume and pHi. On the other hand, PKC appeared to have an impact on NHE-independent pathways affecting intracellular acid-base homeostasis.
...
PMID:Signalling pathways involved in hypertonicity- and acidification-induced activation of Na+/H+ exchange in trout hepatocytes. 1688 59

<< Previous 1 2 3 4 5 6 7 Next >>