Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The translocation of protein kinase C (PKC) isoforms PKC-alpha, PKC-delta, PKC-epsilon, and PKC-zeta from soluble to particulate fractions was studied in ventricular cardiomyocytes cultured from neonatal rats. Endothelin-1 (ET-1) caused a rapid ETA receptor-mediated translocation of PKC-delta and PKC-epsilon (complete in 0.5-1 min). By 3-5 min, both isoforms were returning to the soluble fraction, but a greater proportion of PKC-epsilon remained associated with the particulate fraction. The EC50 of translocation for PKC-delta was 11-15 nM ET-1 whereas that for PKC-epsilon was 1.4-1.7 nM. Phenylephrine caused a rapid translocation of PKC-epsilon (EC50 = 0.9 microM) but the proportion lost from the soluble fraction was less than with ET-1. Translocation of PKC-delta was barely detectable with phenylephrine. Neither agonist caused any consistent translocation of PKC-alpha or PKC-zeta. Activation of p42 and p44 mitogen-activated protein kinase (MAPK) by ET-1 or phenylephrine followed more slowly (complete in 3-5 min). Phosphorylation of p42-MAPK occurred simultaneously with its activation. The proportion of the total p42-MAPK pool phosphorylated in response to ET-1 (50%) was greater than with phenylephrine (20%). In addition to activation of MAPK, an unidentified p85 protein kinase was activated by ET-1 in the soluble fraction whereas an unidentified p58 protein kinase was activated in the particulate fraction.
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PMID:Differential activation of protein kinase C isoforms by endothelin-1 and phenylephrine and subsequent stimulation of p42 and p44 mitogen-activated protein kinases in ventricular myocytes cultured from neonatal rat hearts. 780 10

In renal collecting ducts, endothelin-1 (ET-1) inhibits Na+ reabsorption and antagonizes the effects of arginine vasopressin (AVP). Whether AVP may affect ET-1 action in the collecting ducts that mainly express the ETB receptor subtype, however, remains unknown. Since ETB, but not ETA, possesses a consensus amino acid sequence for possible phosphorylation by protein kinase A (PKA), we hypothesized that AVP may influence ET-1 binding to the ETB receptor via PKA. In microdissected rat cortical collecting ducts, the specific ET-1 binding decreased by 35% (15.6 +/- 4.4 vs. 24.0 +/- 3.6 amol/mm in control) following 20-min preincubation with 10(-7) M AVP. This decrease in ET-1 binding was mimicked by 10(-5) M forskolin and by 10(-4) M dibutyryl (DB) adenosine 3',5'-cyclic monophosphate (cAMP), indicating that this heterologous desensitization may be caused by a cAMP-dependent mechanism. Moreover, N-(2([3-(4-bromophenyl)-2-propenyl]-amino]-ethyl)-5- isoquinolinesulfonamide (H-89) and the Rp diastereoisomer of cAMP, Rp-cAMPS, which are both PKA-specific inhibitors, eliminated AVP-induced ETB receptor desensitization. The reduction in ET-1 binding was characterized by a decrease in binding affinity [dissociation constant (Kd) = 4 vs. 2 nM in control] with no change in maximal binding capacity. In contrast, forskolin and DBcAMP had no effect on ET-1 binding in endothelium-denuded aortic strips, which mainly express ETA subtype. These results showed that AVP rapidly downregulates the ETB receptor by reducing Kd through a PKA-dependent pathway. Thus ET-1 and AVP may act in a mutually antagonizing manner in the renal collecting ducts.
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PMID:Desensitization of endothelin-1 binding by vasopressin via a cAMP-mediated pathway in rat CCD. 790 Aug 37

The vasoactive peptide endothelin-1 (ET-1) dose-dependently increased release of 51Cr from human cerebromicrovascular endothelial cells (HBEC), without affecting cell viability as assessed by lactate dehydrogenase release. ET-1 also induced transient accumulation of inositol triphosphate (IP3) and release of [3H] arachidonic acid (AA) from HBEC. The ET-1-induced 51Cr release, formation of IP3, and AA release from HBEC were competitively inhibited by selective ETA subtype receptor antagonist BQ-123. ET-1-stimulated 51Cr- and AA release from HBEC were potentiated by proteinkinase C (PKC) activator phorbol-myristate ester, and abolished by H7, an inhibitor of PKC. Dexamethasone, indomethacin, acetylsalicylic acid, imidazole, as well as the inhibitor of protein kinase A, H8, had no effect on 51Cr release. The results suggest that ETA-receptor mediated activation of PKC and increase in the HBEC 'permeability' for low molecular weight molecules in response to excessive release of endothelins from either HBEC or surrounding tissues during pathologic conditions may contribute to the formation of cerebral edema.
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PMID:Arachidonic acid release and permeability changes induced by endothelins in human cerebromicrovascular endothelium. 797 60

We have found that ethanol-induced increases in extracellular adenosine activate adenosine receptors which, in turn, mediate many of the acute and chronic effects of ethanol in the nervous system. Several laboratories have demonstrated the importance of adenosine in mediating the acute and chronic effects of ethanol at multiple levels of investigation in the nervous system. These include genetic selection for ethanol sensitivity in mice, behavioral responses to ethanol in naive and tolerant animals, neurophysiologic responses in hippocampal slices, and at the level of cAMP signal transduction and gene expression in cultured neural cells. In this review we present results from our laboratory which document the role of adenosine in mediating ethanol-induced changes in neural function at a cellular and molecular level. A schematic summary of our findings is: Etoh-->decreases Ado uptake-->increases Extracellular Ado-->Activation of Adenosine A2 receptor-->increases cAMP-->increases PKA-->-->-->Heterologous Desensitization (decreases cAMP)-->-->-->insensitivity of adenosine uptake to ETOH
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PMID:The role of adenosine in mediating cellular and molecular responses to ethanol. 803 48

Endothelin-1 is a peptide hormone constitutively secreted by vascular and endocardial endothelial cells. Secretion of endothelin-1 is increased under certain pathophysiological conditions, including coronary vasospasm, cardiac ischaemia and myocardial infarction. We have examined the effect of endothelin-1 on the protein kinase A (PKA)-dependent chloride current in voltage-clamped guinea pig ventricular myocytes. This conductance, induced by catecholamines through beta-adrenergic receptors, counteracts the simultaneously increased L-type calcium current by shortening the action potential duration. We report here that endothelin-1, acting through ETA (endothelin-1-selective) receptors, inhibited the current through a pertussis toxin-sensitive mechanism, analogous to muscarinic receptors, by reducing the intracellular cyclic AMP concentration. This effect of endothelin-1 should help protect the ventricle against potentially arrhythmogenic shortening of the action potential during ischaemia when the circulating levels of catecholamines are increased.
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PMID:Inhibition of the cardiac protein kinase A-dependent chloride conductance by endothelin-1. 751 70

Cultured rat brain capillary endothelial cells expressed a large 86Rb+ uptake component that was dependent on external Na+ and Cl- and that was inhibited by loop diuretics with unusual pharmacological properties: benzmetanide (IC50 = 1-5 microM) = bumetanide (IC50 = 1-5 microM) > piretanide (IC50 = 3-16 microM) = furosemide (IC50 = 7-11 microM). It was activated 2-fold by endothelin-1 (EC50 = 1 nM) and endothelin-3 (EC50 = 9 nM). The actions of endothelins were prevented by BQ-123 (cyclo-(D-Trp-D-Asp-Pro-D-Val-Leu)) in a competitive manner and with a high affinity, thus indicating the involvement of an atypical BQ-123-sensitive, ETA-like receptor that had a high affinity for endothelin-3. Neither protein kinase C nor Ca(2+)-dependent protein kinases mediated the actions of endothelins. Cotransport activity was increased 4-fold by hyperosmotic cell shrinkage. Basal Na(+)-K(+)-Cl- cotransport activity was partially inhibited by isoproterenol and was unaffected by agents that promoted cGMP formation. Calyculin A, an inhibitor of protein phosphatases, stimulated cotransport activity and potentiated the action of endothelin-1, but not that of cell shrinkage. Basal and stimulated cotransport activities were inhibited by genistein, a protein kinase inhibitor with similar potencies, and by staurosporine, which has different potencies. Finally, endothelin-1-stimulated activity was partially and specifically inhibited by interleukin-1. It is concluded that rat brain capillary endothelial cells express a Na(+)-K(+)-Cl- cotransporter that has unique properties and that is regulated by multiple protein kinase/phosphatase systems. It is a target for low concentrations of endothelins and may play a role in brain-to-blood movements of K+.
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PMID:Na(+)-K(+)-Cl- cotransporter of brain capillary endothelial cells. Properties and regulation by endothelins, hyperosmolar solutions, calyculin A, and interleukin-1. 805 Oct 75

To investigate the nuclear signalling pathway induced by endothelin (ET) isopeptides, we have established permanent Chinese hamster ovary (CHO) cell lines, CHO-ETA/fos-lacZ and CHO-ETB/fos-lacZ, that produce both a c-fos-beta-galactosidase fusion protein and either the type A or the type B human ET receptor. These cell lines permitted a colorimetric measurement of c-fos expression, which was induced by the signal transduction system with ET receptors and ET isopeptides. We found that the ET-1-dependent c-fos expression was so efficient that it could respond to low concentrations (even a physiological concentration) of ET-1. For example, CHO-ETA/fos-lacZ and CHO-ETB/fos-lacZ responded to ET concentrations of 5 x 10(-9) M and 5 x 10(-13) M respectively. Using this highly sensitive system, the H-7 sensitive protein kinase was found to be involved in signal transduction mediated by ETA, and also partly in the ETB-mediated pathway. These lines of evidence suggest that c-fos expression occurs through at least two different pathways, depending on the concentration of ET in plasma.
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PMID:Differential regulation of c-fos gene expression by two types of human endothelin receptor in Chinese hamster ovary cells. 806 Apr 82

The vasoactive peptides endothelin-1 (ET-1) and angiotensin-II (AII) have been implicated in chronic hypertension and may play important roles in related vascular diseases such as restenosis and atherosclerosis. Using a rat aortic smooth muscle (RASM) cell model, both ET-1 and AII induced concentration-dependent delayed increases in DNA synthesis relative to that in the serum-deprived controls. Stimulation of DNA synthesis was maximal at 100 nM for each peptide. All treatment of RASM cells resulted in a greater mitogenic effect (4- to 7-fold) than that observed for ET-1 (3-fold). When added in the presence of AII, ET-1 had a supplemental effect on DNA synthesis (5- to 10-fold above control). Although RASM cells expressed both ETA and AT1 receptors, radioligand binding experiments indicated that approximately 10-fold as many AT1 receptors as ETA receptors were present. In signal transduction studies, ET-1 and AII each elicited concentration-dependent increases in the intracellular Ca2+ concentration. ET-1 and AII also stimulated phosphoinositide metabolism and phosphorylation of a specific substrate for protein kinase-C. The release of total inositol phosphates in response to ET-1 and AII was concentration dependent and inhibited by the ETA receptor-selective antagonist BQ-123 and the AT1 receptor-selective antagonist losartan, respectively. In addition, tyrosine phosphorylation of 120- and 75-kilodalton proteins as well as the mitogen-activated protein kinases p44mapk and p42mapk was observed within 5 min of the addition of either ET-1 or AII. Taken together, these data indicate that ET-1 and AII may promote smooth muscle cell growth through common intracellular signaling mechanisms.
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PMID:Endothelin-1 and angiotensin-II stimulate delayed mitogenesis in cultured rat aortic smooth muscle cells: evidence for common signaling mechanisms. 817 Apr 71

The effects of endothelins (ET) on the proliferative activity of the rat adrenal cortex have been investigated in vivo, using an in situ perfusion technique of the intact left gland. The chemicals were dissolved in the perfusion medium, and the perfusion continued for 120 min. ET-1 concentration dependently increased the mitotic index and [3H]thymidine incorporation into DNA in the zona glomerulosa (ZG; 6- and 3-fold increases, respectively, at a 10(-8) M concentration), but not in the inner adrenocortical layers, where the basal proliferative activity was negligible. The effect of 10(-8) M ET-1 was blocked by the ETA receptor antagonist BQ-123, whereas the ETB receptor antagonist BQ-788 was ineffective. ET-2 and ET-3 (10(-8) M) enhanced DNA synthesis in the ZG, but their effects were less intense than that of 10(-8) M ET-1 and were directly related to their binding potency for the ETA receptor subtype (ET-1 > ET-2 >> ET-3). The selective ETB receptor agonists BQ-3020, IRL-1620, and sarafotoxin-6B were ineffective. The ZG proliferogenic action of 10(-8) M ET-1 was reversed by both the protein kinase C inhibitor Ro31-8220 and the tyrosine kinase inhibitor tyrphostin-23; a complete blockade was obtained at a 10(-6)-M concentration of each inhibitor. In contrast, neither the protein kinase A inhibitor H-89 (10(-5) M) nor the cyclooxygenase and lipoxygenase inhibitors indomethacin and phenidone (10(-5) M) affected ET-1 action. Collectively, our findings indicate that ETs stimulate the proliferation of rat adrenal ZG cells, acting through ETA receptors coupled with protein kinase C- and tyrosine kinase-dependent signaling pathways. The results of the present study are in keeping with the view that in mammals, ZG is the proliferative layer involved in the maintenance of growth of the entire adrenal cortex and with the previous autoradiographic demonstration that ZG is the only adrenocortical layer provided with ETA receptors.
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PMID:Endothelins stimulate deoxyribonucleic acid synthesis and cell proliferation in rat adrenal zona glomerulosa, acting through an endothelin A receptor coupled with protein kinase C- and tyrosine kinase-dependent signaling pathways. 916 19

Endothelin-1 (ET-1) is a 21-amino acid peptide hormone released from myocardial and endothelial cells, whose receptors (both ETA and ETB are expressed in the myocardium. We report here that ET-1 inhibits the cardiac delayed rectifier K+ current (IK) via a pertussis toxin (PTX)-sensitive mechanism. Ventricular myocytes enzymatically isolated from guinea pig hearts were voltage-clamped by the conventional whole-cell and nystatin-perforated patch technique (intrapipette and extrapipette K+ concentrations, 150 and 5.4 mmol/L, respectively) in the presence of nifedipine (2 mumol/L). Amplitudes of tail and steady state (2-second pulse) currents were measured as IK. ET-1 suppressed the basal IK by 20.9 +/- 2.3% in a concentration-dependent manner, with an IC50 of 1.1 +/- 0.3 nmol/L (n = 19), although it did not suppress the basal IK using the nystatin method. E-4031 (5 mumol/L), a blocker of the rapid component of IK (IKr), did not prevent the inhibitory action of ET-1. ET-1 reduced by 63.4 +/- 6.5% the slow component of IK (IKs) that had been enhanced to approximately 2-fold by isoproterenol (ISO, 20 nmol/L). The action was concentration dependent, with an IC50 of 0.7 +/- 0.4 nmol/L (n = 22), and was also observed using the nystatin method. The effect of ET-1 appeared to be mediated by an ETA receptor, because it was prevented by FR139317, an ETA-selective antagonist (1 mumol/L, n = 4), and sarafotoxin s6c, an ETB-selective agonist (100 nmol/L, n = 4), could not inhibit the ISO-enhanced IK. ET-1 antagonized IKs enhanced by histamine (250 nmol/L, n = 7) and forskolin (500 nmol/L, n = 7) but did not inhibit IKs enhanced by the internal application of cAMP (100 mumol/L, n = 6). Preincubation of myocytes with PTX (5 micrograms/mL for > 60 minutes at 36 degrees C) completely abolished the inhibitory action of ET-1 on the ISO-enhanced IKs (n = 4). Thus, nanomolar ET-1 inhibits IKs via the ETA receptor/PTX-sensitive G protein/PKA pathway.
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PMID:Endothelin-1 inhibits the slow component of cardiac delayed rectifier K+ currents via a pertussis toxin-sensitive mechanism. 924 82


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