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)

In this paper we review three intra-luteal factors and their roles in the corpus luteum (CL). Insulin-like growth factor (IGF)-I, together with its receptor and IGF-binding proteins (IGFBPs), represent an important control system in the CL. IGF-I is a product of small luteal cells and has steroidogenic (i.e. luteotrophic) actions on large luteal cells via the type I receptor, while IGFBPs (e.g. BP-2 and 3; small cells) generally inhibit IGF-Is actions. IGF-I is particularly important in early CL development (up to day 7 of the oestrous cycle) in the pig. Tumour necrosis factor (TNF)-alpha is a product of luteal macrophages that infiltrate CLs in increasing numbers as the cycle progresses. TNF-alpha has been shown to play an important role in luteolysis, but we hypothesise that in the pig, this factor plays an additional role during the mid-luteal phase (days 7-13) in promoting the acquisition of luteal sensitivity to the luteolytic actions of prostaglandin (PG)F2alpha (= luteolytic sensitivity; LS). Endothelin (ET)-1 is a product of (luteal) endothelial cells, and along with its receptors (ETA and ETB) and endothelin-converting enzyme (ECE)-1, represent an intra-luteal system that also plays a role in luteolysis, in association with PGF2alpha. Since TNF-alpha induces endothelial cells to secrete ET-1, we hypothesise that ET-1 mediates the sensitising effects of TNF-alpha on the porcine CL during the mid-luteal phase (days 7-13). Finally, we hypothesise that TNF-alpha and/or ET-1 act to up-regulate luteal protein kinase C (e.g. isoforms betaII and epsilon) activity and thereby sensitises luteal cells to PGF2alpha.
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PMID:The role of intra-luteal factors in the control of the porcine corpus luteum. 1686 10

Endothelins (ETs) exert a persistent constrictor effect on the vessels via an increase in intracellular Ca2+ concentration due to the activation of Na+/H+ and Na+/Ca2+ exchangers of the vascular smooth muscle fibres. They also produce a transient dilator effect via the activation of endothelial nitric oxide synthase mediated by protein kinase B/Akt. ETA and ETB2 receptors are involved in vasoconstriction, whereas transient vasodilatation depends on the activation of ETB1 receptors. Depending on animal species and experimental conditions, ETs can also play a role in cardiac muscle contraction and induce either an increase or a decrease in contractility. It is likely that only ETA, and not ETB, receptors are involved in the ET-induced increase in myocardial contractility. As in the case of vasoconstriction, this inotropic effect depends on an increase in intracellular Ca2+ concentration induced by Na+/H+ and Na+/Ca2+ exchangers. Activation of the Na+/H+ exchanger is stimulated by protein kinase C, which is activated by diacylglycerol released in response to ET activity. It has also been proposed that the positive inotropic effect can occur without the contribution of the Na+/Ca2+ exchanger, if the cell alkalinisation produced by the Na/H exchanger improves myofibrillar Ca2+ sensitivity. A reduction in contractility has been attributed to the involvement of the Gi protein/protein kinase G pathway or to the activation of protein kinase C without an increase in intracellular Ca2+ concentration or in myofibrillar Ca2+ sensitivity. The chronic effect of ETs on the myocardium results in hypertrophy and prevention of apoptosis, two processes that are together responsible for the contradictory effect of ETs in heart failure.
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PMID:Effect of endothelins on the cardiovascular system. 1693 76

T-type Ca2+ channels play essential roles in numerous cellular processes. Recently, we reported that phorbol-12-myristate-13-acetate (PMA) potently enhanced the current amplitude of Cav3.2 T-type channels reconstituted in Xenopus oocytes. Here, we have compared PMA modulation of the activities of Cav3.1, Cav3.2 and Cav3.3 channels, and have investigated the underlying mechanism. PMA augmented the current amplitudes of the three T-type channel isoforms, but the fold stimulations and time courses differed. The augmentation effects were not mimicked by 4alpha-PMA, an inactive stereoisomer of PMA, but were abolished by preincubation with protein kinase C (PKC) inhibitors, indicating that PMA augmented T-type channel currents via activation of oocyte PKC. The stimulation effect on Cav3.1 channel activity by PKC was mimicked by endothelin when endothelin receptor type A was coexpressed with Cav3.1 in the Xenopus oocyte system. Pharmacological studies combined with fluorescence imaging revealed that the surface density of Cav3.1 T-type channels was not significantly changed by activation of PKC. The PKC effect on Cav3.1 was localized to the cytoplasmic II-III loop using chimeric channels with individual cytoplasmic loops of Cav3.1 replaced by those of Cav2.1.
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PMID:Activation of protein kinase C augments T-type Ca2+ channel activity without changing channel surface density. 1700 78

The ATP-driven drug efflux pump, P-glycoprotein, is a critical and selective element of the blood-brain barrier and a primary impediment to pharmacotherapy of central nervous system (CNS) disorders. Thus, an understanding of how P-glycoprotein function is regulated has the potential to improve CNS therapy. We recently demonstrated rapid (minutes) and reversible inactivation of P-glycoprotein in rat brain capillaries signaled through tumor necrosis factor-alpha (TNF-alpha) and endothelin-1 (ET-1), components of the brain's innate immune response. In this study, we examined the longer-term consequences of continuous exposure of rat brain capillaries to low levels of TNF-alpha and ET-1. Exposing brain capillaries to TNF-alpha or ET-1 caused a rapid decrease in P-glycoprotein transport activity with no change in transporter protein expression. This was followed by a 2- to 3-h plateau at the low activity level and then by a sharp increase in both transport activity and protein expression. After 6 h, transport activity and transporter protein expression was double that of control samples. TNF-alpha signaled through TNF-R1, which in turn caused ET release and action through ETA and ETB receptors, nitric-oxide synthase, protein kinase C and nuclear factor-kappaB (NF-kappaB) and finally increased P-glycoprotein expression and transport activity. Assuming similar effects occur in vivo, the present results imply a tightening of the selective blood-brain barrier with chronic inflammation and thus reduced efficacy of CNS-acting drugs that are P-glycoprotein substrates. Moreover, involvement of NF-kappaB raises the possibility that other effectors acting through this transcription factor may have similar effects on this key blood-brain barrier transporter.
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PMID:Tumor necrosis factor alpha and endothelin-1 increase P-glycoprotein expression and transport activity at the blood-brain barrier. 1713 86

Endothelin-1 (ET-1), a vasoactive peptide, is believed to contribute to the pathogenesis of vascular abnormalities such as hypertension, atherosclerosis, hypertrophy and restenosis. ET-1 elicits its biological effects through the activation of two receptor subtypes, ET-A and ET-B that belong to a large family of transmembrane guanine nucleotide-binding protein-coupled receptors (GPCRs). ET-1 receptor activation results in the stimulation of several signaling pathways including mitogen-activated protein kinases (MAPKs), phosphatidylinositol 3-kinase (PI3-K) and protein kinase B (PKB). An intermediary role of Ca(2+)/calmodulin-dependent protein kinases (CaMK), protein kinase C (PKC) as well as receptor and non-receptor protein tyrosine kinases in triggering the activation of MAPK and PI3-K/PKB signaling in response to ET-1 has been suggested. Activation of these pathways by ET-1 is intimately linked with the regulation of cellular hypertrophy, growth, proliferation and cell survival. Here we provide an overview of these signaling pathways in vascular smooth muscle cells (VSMCs) with an emphasis on their potential role in vascular pathophysiology.
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PMID:Endothelin-1-induced signaling pathways in vascular smooth muscle cells. 1726 12

Endothelin-1 (ET-1) regulates contractility and growth of the mammalian heart by binding endothelin receptor type A (ET(A)) and endothelin receptor type B (ET(B)) G-protein-coupled receptors. To identify growth signaling pathways associated with ET-1 receptors in adult myocardium, a combined immunoprecipitation/proteomic analysis was performed. Signaling proteins believed to function downstream of ET(A) such as Galpha(q), phospholipase C-beta1, protein kinase C (PKC) epsilon, and PKCdelta were identified in immunoprecipitates of ET(A) by matrix-assisted laser desorption ionization/time of flight mass spectrometry. Also prominent were the growth factor receptor tyrosine kinases erbB2 and erbB4 and their downstream growth signaling effectors phosphoinositide-3 kinase (PI3 kinase), Akt, Raf-1, mitogen-activated protein kinase kinase (MEK), and extracellular signal-regulated kinase (Erk). Western blot analysis confirmed coimmunoprecipitation of erbB2/4, PI3 kinase, and Akt with ET(A), and confocal microscopy revealed their colocalization in cardiac transverse tubules (T-tubules). The erbB4 receptor ligand neuregulin-1beta (NRG1beta) promoted erbB2/4 tryosine phosphorylation and Akt serine phosphorylation in ventricular myocytes, whereas treatment with ET-1 did not. This observation argues against ET-1 growth signaling occurring via erbB2/4 transactivation in adult myocardium. ET-1 did, however, stimulate Erk1/2 phosphorylation and substantially blunted several NRG1beta-mediated actions, including erbB2/4 phosphorylation, serine phosphorylation of Akt, and negative inotropy. This inhibitory cross-talk between ET(A) and erbB2/4-Akt pathways was mimicked by a phorbol ester and blocked by pharmacological inhibition of PKC or MEK/Erk. The proteomic analysis and subsequent investigation of receptor cross-talk indicate that growth signaling between ET(A) and erbB pathways is fundamentally different in adult versus neonatal cardiac myocytes. The results may be relevant to cardiomyopathies associated with 1) prolonged exposure to ET-1; 2) degeneration of T-tubules; and 3) therapies targeted at erbB2 inhibition.
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PMID:Interaction and inhibitory cross-talk between endothelin and ErbB receptors in the adult heart. 1733 41

Given that vascular endothelial cells play an important role in the modulation of vascular structure and function, we hypothesized that endocardial endothelial cells (EECs) may have a modulator role in regulating the cardiac interstitial cells. Endocardial endothelial cells were isolated from freshly collected pig hearts and cardiac fibroblasts were isolated from 3- to 4-d-old Wistar rats. Fibroblasts were cultured in the presence or absence of conditioned medium from EECs. Proliferation of cardiac fibroblasts was measured by the incorporation of [3H]- Thymidine and collagen synthesis was assayed by the incorporation of [3H]-Proline. To determine the involvement of signaling mediators, in separate experiments, cardiac fibroblasts were incubated with BQ123 (selective ETA receptor antagonist), PD142893 (nonselective ETA/ETB receptor antagonist), Bis-indolylmaleimide (PKC inhibitor), PD 098059 (MEK inhibitor), or neutralizing anti-transforming growth factor (TGF)-beta-antibody. Endocardial endothelium-derived factors endothelin (ET)-1, TGF-beta, and Angiotensin (Ang)-II in the conditioned medium were assayed by enzyme-linked immunosorbent assay using commercially available kits. We report here evidence that suggest that endocardial endothelial cells stimulate both proliferation and collagen synthesis of cardiac fibroblasts. The response seems to be mediated by endothelin through its ETA receptor. Our results also indicate that protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) pathways are essential for the EEC-induced proliferation of cardiac fibroblasts.
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PMID:Endocardial endothelial cells stimulate proliferation and collagen synthesis of cardiac fibroblasts. 1740 60

We used patch-clamp electrophysiology to investigate regulation of the epithelial Na+ channel (ENaC) by endothelin-1 (ET-1) in isolated, split-open rat collecting ducts. ET-1 significantly decreases ENaC open probability by about threefold within 5 min. ET-1 decreases ENaC activity through basolateral membrane ETB but not ETA receptors. In rat collecting duct, we find no role for phospholipase C or protein kinase C in the rapid response of ENaC to ET-1. ET-1, although, does activate src family tyrosine kinases and their downstream MAPK1/2 effector cascade in renal principal cells. Both src kinases and MAPK1/2 signaling are necessary for ET-1-dependent decreases in ENaC open probability in the split-open collecting duct. We conclude that ET-1 in a physiologically relevant manner rapidly suppresses ENaC activity in native, mammalian principal cells. These findings may provide a potential mechanism for the natriuresis observed in vivo in response to ET-1, as well as a potential cause for the salt-sensitive hypertension found in animals with impaired endothelin signaling.
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PMID:Regulation of the epithelial Na+ channel by endothelin-1 in rat collecting duct. 1866 82

Our previous work showed that ET-1 induced a concentration-dependent increase of cytosolic Ca2+ ([Ca]c) and nuclear Ca2+ ([Ca]n) in human aortic vascular smooth muscle cells (hVSMCs). In the present study, using hVSMCs and 3-dimensional confocal microscopy coupled to the Ca2+ fluorescent probe Fluo-3, we showed that peptidic antagonists of ETA and ETB receptors (BQ-123 (10(-6) mol/L) and BQ-788 (10(-7) mol/L), respectively) prevented, but did not reverse, ET-1-induced sustained increase of [Ca]c and [Ca]n. In contrast, nonpeptidic antagonists of ETA and ETB (respectively, BMS-182874 (10(-8)-10(-6) mol/L) and A-192621 (10(-7) mol/L)) both prevented and reversed ET-1-induced sustained increase of [Ca]c and [Ca]n. Furthermore, activation of the ETB receptor alone using the specific agonist IRL-1620 (10(-9) mol/L) induced sustained increases of [Ca]c and [Ca]n, and subsequent administration of ET-1 (10(-7) mol/L) further increased nuclear Ca2+. ET-1-induced increase of [Ca]c and [Ca]n was completely blocked by extracellular application of the Ca2+ chelator EGTA. Pretreatment with the G protein inhibitors pertussis toxin (PTX) and cholera toxin (CTX) also prevented the ET-1 response; however, strong membrane depolarization with KCl (30 mmol/L) subsequently induced sustained increase of [Ca]c and [Ca]n. Pretreatment of hVSMCs with either the PKC activator phorbol-12,13-dibutyrate or the PKC inhibitor bisindolylmaleimide did not affect ET-1-induced sustained increase of intracellular Ca2+. These results suggest that both ETA- and ETB-receptor activation contribute to ET-1-induced sustained increase of [Ca]c and [Ca]n in hVSMCs. Moreover, in contrast to the peptidic antagonists of ET-1 receptors, the nonpeptidic ETA-receptor antagonist BMS-182874 and the nonpeptidic ETB-receptor antagonist A-192621 were able to reverse the effect of ET-1. Nonpeptidic ETA- and ETB-receptor antagonists may therefore be better pharmacological tools for blocking ET-1-induced sustained increase of intracellular Ca2+ in hVSMCs. Our results also suggest that the ET-1-induced sustained increase of [Ca]c and [Ca]n is not mediated via activation of PKC, but via a PTX- and CTX-sensitive G protein calcium influx through the R-type Ca2+ channel.
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PMID:Nonpeptidic antagonists of ETA and ETB receptors reverse the ET-1-induced sustained increase of cytosolic and nuclear calcium in human aortic vascular smooth muscle cells. 1875 3

Using fura-2-acetoxymethyl ester (AM) fluorescence imaging and patch clamp techniques, we found that endothelin-1 (ET-1) significantly elevated the intracellular calcium level ([Ca(2+)](i)) in a dose-dependent manner and activated the L-type Ca(2+) channel in cardiomyocytes isolated from rats. The effect of ET-1 on [Ca(2+)](i) elevation was abolished in the presence of the ET(A) receptor blocker BQ123, but was not affected by the ET(B) receptor blocker BQ788. ET-1-induced an increase in [Ca(2+)](i), which was inhibited 46.7% by pretreatment with a high concentration of ryanodine (10 micromol/L), a blocker of the ryanodine receptor. The ET-1-induced [Ca(2+)](i) increase was also inhibited by the inhibitors of protein kinase A (PKA), protein kinase C (PKC) and angiotensin type 1 receptor (AT1 receptor). We found that ET-1 induced an enhancement of the amplitude of the whole cell L-type Ca(2+) channel current and an increase of open-state probability (NPo) of an L-type single Ca(2+) channel. BQ123 completely blocked the ET-1-induced increase in calcium channel open-state probability. In this study we demonstrated that ET-1 regulates calcium overload through a series of mechanisms that include L-type Ca(2+) channel activation and Ca(2+)-induced Ca(2+) release (CICR). ETA receptors, PKC, PKA and AT1 receptors may also contribute to this pathway.
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PMID:Endothelin-1 induces intracellular [Ca2+] increase via Ca 2+ influx through the L-type Ca2+ channel, Ca 2+ -induced Ca2+ release and a pathway involving ET A receptors, PKC, PKA and AT1 receptors in cardiomyocytes. 1938 62


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