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)

We examined the regulatory mechanisms of endothelin-1 (ET-1) production in cultured rat vascular smooth muscle cells (VSMC) with a special focus on the roles of protein kinase C (PKC)- and cyclic guanosine-3',5'-monophosphate (GMP)-mediated signaling systems. Effects of atrial, brain, and C-type natriuretic peptides (ANP, BNP, and CNP) on angiotensin II (Ang II)-, and arginine vasopressin (AVP)-induced production of ET-1 were examined in cultured rat aortic VSMC. Ang II and AVP stimulated ET-1 production in a concentration-dependent manner through angiotensin subtype 1 (AT1) and vasopressin subtype 1 (V1) receptors, respectively. The stimulatory effects of Ang II and AVP were markedly abolished in PKC-depleted cells. Rat ANP (1-28), rat BNP-45, and rat CNP-22 potently inhibited Ang II- and AVP-stimulated ET-1 production in a concentration-dependent manner, respectively. The inhibitory effect by CNP on ET-1 production was paralleled by an increase in the cellular level of cyclic GMR.8-Bromo cyclic GMP reduced the stimulated ET-1 production by Ang II and AVP. These results indicate that Ang II and AVP stimulate ET-1 production in cultured rat VSMC through AT1 and V1 receptors by a mechanism probably involving activation of PKC, and that ANP, BNP, and CNP inhibit this stimulated production through a cyclic GMP-dependent process.
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PMID:Endothelin production in cultured vascular smooth muscle cells--modulation by the atrial, brain, and C-type natriuretic peptide system. 916 Aug 12

In the medullary thick ascending limb (MTAL) of the rat kidney, prostaglandin E2 (PGE2) reverses inhibition of HCO3 absorption by arginine vasopressin (AVP). This effect of PGE2 is blocked by chelerythrine or staurosporine and mimicked by phorbol ester, suggesting a critical role for protein kinase C (PKC). The present study was designed to examine directly regulation of PKC isoforms by PGE2 in the inner stripe of the outer medulla and in microdissected MTALs. Immunoblots with isoform-specific anti-PKC antibodies detected alpha-, beta II-, delta-, epsilon-, and zeta-isoforms in both inner stripe and MTAL. The beta I- and gamma-isoforms were not detected. Translocation and activation of PKC were assessed by immunoblot analysis and by direct measurement of enzyme activity using an immune complex kinase assay. In inner stripe tissue incubated with 10(10) M AVP, PGE2 10(6) M for 20 min) induced translocation of PKC-delta from the cytosolic fraction to the membrane fraction. This translocation was associated with an 85% increase in PKC-delta activity in the membrane fraction and a 70% decrease in PKC-delta activity in the cytosolic fraction. PGE2 had no effect on the subcellular distribution or the activities of the other isoforms. Activation of PKC-delta was confirmed directly in microdissected MTALs, in which PGF2 caused a near complete loss of PKC-delta from the cytosolic fraction. PGE2 did not induce translocation of PKC-delta in the absence of AVP. These results demonstrate that 1) the MTAL expresses Ca(2+)-dependent (alpha, beta II) and Ca(2+)-independent (delta, epsilon, zeta) PKC isoforms; 2) PGE2 causes selective activation of PKC-delta, which likely mediates the action of PGE2 to reverse AVP inhibition of HCO-3 absorption; and 3) PGE2 activation of PKC-delta requires the presence of AVP, which may explain the fact that PGE2 influences HCO-3 transport only when AVP is present.
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PMID:PKC isoforms in rat medullary thick ascending limb: selective activation of the delta-isoform by PGE2. 917 73

The influence of arginine vasopressin (AVP) on agonist-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) accumulation was investigated in vascular smooth muscle cells (VSMC) cultured from rat thoracic aorta. Incubation of VSMC with AVP for 60 s produced a 2- to 2.5-fold enhancement of isoproterenol-induced cAMP formation. AVP also increased cAMP stimulation by the prostaglandin I2 analogue iloprost. The effect of AVP to enhance agonist-stimulated cAMP formation was completely inhibited in cells pretreated with a selective antagonist of V1 vasopressin receptors but was not affected by blockade of V2 receptors. Inhibition of protein kinase C activation failed to alter the action of AVP to potentiate cAMP stimulation, but treatment of cells with calmodulin antagonists significantly attenuated this effect of the peptide. Moreover, depletion of Ca2+ stores with thapsigargin decreased AVP enhancement of isoproterenol-stimulated cAMP by > 70%. The action of AVP to increase cAMP stimulation was also demonstrated in freshly isolated strips of rat aorta where treatment with peptide produced a twofold increase in isoproterenol-stimulated cAMP formation. RNA blot analysis indicated expression in VSMC of mRNA encoding type III adenylyl cyclase, a Ca(2+)-calmodulin-sensitive isoform of the effector. Furthermore, when detergent-solubilized membrane extract was subjected to calmodulin affinity chromatography, a peak of adenylyl cyclase activity was identified which had affinity for calmodulin matrix in the presence of Ca2+. The results indicate that AVP activates V1 receptors in VSMC to enhance agonist-stimulated cAMP formation by a Ca(2+)-calmodulin-dependent mechanism and suggest that type III adenylyl cyclase may provide a focal point in the VSMC for cross talk between constrictor and dilator pathways.
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PMID:Adenylyl cyclase isoforms and vasopressin enhancement of agonist-stimulated cAMP in vascular smooth muscle cells. 927 17

The purpose of this study was to investigate the effects of arginine vasopressin (AVP) on nitric oxide (NO) synthesis in vascular smooth muscle cells (VSMCs). We measured the production of nitrite, a stable metabolite of NO, and the expression of inducible NO synthase (iNOS) mRNA in cultured rat VSMCs. Incubation of VSMCs for 24 h with interleukin-1 beta (IL-1 beta) caused a significant increase in NO production. Both AVP and the V1a receptor agonist [Phe2, Ile3, Orn8]vasopressin inhibited NO synthesis in IL-1 beta-stimulated cells, but not in unstimulated cells, in a dose-dependent manner. The V1a receptor antagonist [d(CH2)5(1), O-Me-Tyr2, Arg8]vasopressin completely inhibited the effect of AVP. Incubation with IL-1 beta for 24 h induced the expression of iNOS mRNA in VSMCs, while AVP suppressed its expression. After functional depletion of protein kinase C activity by treating cells with phorbol 12-myristate 13-acetate for 24 h, AVP did not inhibit IL-1 beta-induced NO production. The effect of AVP was also inhibited in the presence of the protein kinase C inhibitor calphostin C in a dose-dependent manner. These results indicate that AVP inhibits IL-1 beta-induced iNOS expression in VSMCs through the V1a receptor, which is mediated at least partially via activation of protein kinase C.
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PMID:Arginine vasopressin inhibits nitric oxide synthesis in cytokine-stimulated vascular smooth muscle cells. 932 2

These studies were conducted to determine if the prostaglandin-synthesis inhibitor indomethacin or the protein kinase C (PKC) inhibitor staurosporine affect the inhibition of osmotic water permeability (Pf) by the alpha-2 (alpha 2) agonist dexmedetomidine in the rat inner medullary collecting duct (IMCD). Terminal IMCDs from Wistar rats were perfused and Pf was increased with either 220 pM arginine vasopressin (AVP) or 0.1 mM 8-chlorophenylthio cyclic adenosine monophosphate (8CPTcAMP). All agents were added to the bathing solution. Dexmedetomidine at 100 nM inhibited both AVP- and 8CPTcAMP-stimulated Pf. When Pf was increased by AVP, indomethacin at 0.1 mM or 5 microM reversed the dexmedetomidine-induced inhibition by 68% and 43%, respectively. When Pf was increased by 8CPTcAMP, indomethacin at 0.1 mM or 5 microM reversed inhibition by 83% and 70%, respectively. Indomethacin increased AVP and 8CPTcAMP-stimulated Pf by 20 to 30% and dexmedetomidine inhibited the AVP+ indomethacin-stimulated Pf. Staurosporine at 10 nM yielded similar results. Results suggest that PKC and prostaglandins are involved in the alpha 2 mediated mechanism, and staurosporine and indomethacin-sensitive cellular mediators modulate basal Pf.
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PMID:Indomethacin and staurosporine reverse alpha 2 inhibition of water transport in rat IMCD. 935 Jun 58

We investigated the effects of arginine vasopressin (AVP) on nitric oxide (NO) synthase activity in cardiac myocytes by measuring the production of nitrite, a stable metabolite of NO, and the expression of inducible NO synthase (iNOS) mRNA and protein. Incubation of cultured neonatal rat cardiac myocytes for 24 hours with interleukin-1beta (IL-1beta) caused a significant increase in NO production. Both AVP and V1a receptor agonist [Phe2,Ile3,Orn8]vasopressin augmented NO synthesis in IL-1beta-stimulated, but not in unstimulated myocytes, in a dose-dependent manner. The V1a receptor antagonist [d(CH2)[5]1,O-Me-Tyr2,Arg8]vasopressin completely inhibited the effect of AVP. The AVP-induced NO production by IL-1beta-stimulated cells was accompanied by increased iNOS mRNA and protein accumulation. AVP caused a significant increase in cytosolic free Ca2+ levels of cardiac myocytes, whereas it showed no effect on cytosolic cAMP levels. After protein kinase C activity was functionally depleted by treating cells with phorbol 12-myristate 13-acetate for 24 hours, AVP did not augment IL-1beta-induced NO production. The effect of AVP was also inhibited in the presence of the protein kinase C inhibitor calphostin C. The addition of AVP increased protein kinase C activity in cardiac myocytes, and its effect was significantly inhibited in the presence of calphostin C. These results support the hypothesis that the heart may be a target organ for AVP and that AVP modulates IL-1beta-induced iNOS expression in myocytes through the V1a receptor, which is mediated at least partially via activation of protein kinase C.
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PMID:Arginine vasopressin increases nitric oxide synthesis in cytokine-stimulated rat cardiac myocytes. 936 64

Protein synthesis in H9c2 ventricular myocytes was subject to rapid inhibition by agents that release Ca2+ from the sarcoplasmic/endoplasmic reticulum, including thapsigargin, ionomycin, caffeine, and arginine vasopressin. Inhibitions were attributable to the suppression of translational initiation and were coupled to the mobilization of cell-associated Ca2+ and the phosphorylation of eIF2alpha. Ionomycin and thapsigargin produced relatively stringent degrees of Ca2+ mobilization that produced an endoplasmic reticulum (ER) stress response. Translational recovery was associated with the induction of ER chaperones and resistance to translational inhibition by Ca2+-mobilizing agents. Vasopressin at physiologic concentrations mobilized 60% of cell-associated Ca2+ and decreased protein synthesis by 50% within 20-30 min. The inhibition of protein synthesis was exerted through an interaction at the V1 vascular receptor, was imposed at physiologic extracellular Ca2+ concentrations, and became refractory to hormonal washout within 10 min of treatment. Inhibition was found to attenuate after 30 min, with full recovery occurring in 2 h. Translational recovery did not involve an ER stress response but rather was derived from the partial repletion of intracellular Ca2+ stores. Longer exposures to vasopressin were invariably accompanied by increased rates of protein synthesis. Translational inhibition by vasopressin, but not by Ca2+-mobilizing drugs, was both preventable and reversible by treatment with phorbol ester, which reduced the extent of Ca2+ mobilization occurring in response to the hormone. Larger and more prolonged translational inhibitions occurred after down-regulation of protein kinase C. This report provides the first compelling evidence that hormonally induced mobilization of sarcoplasmic/endoplasmic reticulum Ca2+ stores is regulatory upon mRNA translation.
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PMID:Regulation of protein synthesis in ventricular myocytes by vasopressin. The role of sarcoplasmic/endoplasmic reticulum Ca2+ stores. 945 7

Previous studies in microdissected rat inner medullary collecting duct (IMCD) segments have demonstrated that carbachol, arginine vasopressin (AVP), and the V2 vasopressin receptor agonist 1-desamino-8-D-arginine vasopressin (DDAVP) induce a similar increase in intracellular Ca2+. The present study tested whether these agents activate the phosphoinositide hydrolysis pathway. In intracellular inositol 1,4,5-trisphosphate (IP3) measurements, we found that IMCD suspensions incubated with AVP or DDAVP (10(-8) M) displayed no measurable increase in IP3, whereas IMCD suspensions incubated with the muscarinic cholinergic agent carbachol (100 microM) induced a significant increase in IP3 production. Similarly, carbachol, but not AVP or DDAVP, induced a significant increase in membrane-associated protein kinase C (PKC) enzyme activity. To test what specific PKC isoforms are activated by carbachol in IMCD, we first characterized the PKC isoforms in IMCD suspensions by immunoblotting using affinity-purified antibodies against different PKC isoforms. We identified one classic PKC isoform (alpha), three novel PKC isoforms (delta, epsilon, eta), and one atypical PKC isoform (zeta) in the IMCD. Carbachol induced a cytosol-to-membrane translocation of the PKC-eta isoform but did not alter the distribution of any other isoform. In contrast, AVP had no effect on the distribution of any PKC isoform tested. These data, taken together, demonstrate that carbachol is an activator of the phosphoinositide hydrolysis pathway in IMCD but do not demonstrate signaling via this pathway in response to AVP or DDAVP. These results suggest that the previously observed AVP-stimulated Ca2+ mobilization in IMCD may be due to a mechanism other than activation of the phosphoinositide hydrolysis pathway.
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PMID:Phosphoinositide signaling in rat inner medullary collecting duct. 953 Feb 73

Recent studies indicate that the actions of arginine vasopressin (AVP) and other agonists that stimulate electrogenic sodium transport in renal epithelial A6 cells are linked to a Ca(2+)-mobilizing signal transduction mechanism that involves generation of inositol trisphosphate. Since diacylglycerol is the other product in this pathway, studies were performed to determine the possible role of PKC in the stimulation of sodium transport. AVP induced a biphasic increase in diacylglycerol generation, characterized by an initial rapid rise and then a sustained elevation, and PKC activation, reflected by phosphorylation of a specific 80 kDa myristoylated alanine-rich PKC substrate (MARCKS). To determine the PKC isoform(s) involved in this process, immunoblot analysis was performed using antisera that recognize both classical PKC isoforms, XPKC-I and XPCK-II, cloned from Xenopus oocytes. The transcripts of both isoforms were expressed in the A6 cell. Since protein recognized by antisera was translocated from cytosol to the particulate fraction after exposure to AVP, one or both isoforms were activated in the A6 cell. Further studies showed that cyclohexyladenosine and insulin, additional agonists of sodium transport in A6 cells, also stimulated phosphorylation of MARCKS. These results argue that Ca(2+)-dependent PKC is involved in the action of AVP, and that of other agonists, which stimulate sodium transport.
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PMID:Vasopressin-induced activation of protein kinase C in renal epithelial cells. 956 4

Growth factors stimulate Na+/H+ exchange activity in many cell types but their effects on acid secretion via this mechanism in renal tubules are poorly understood. We examined the regulation of HCO3- absorption by nerve growth factor (NGF) in the rat medullary thick ascending limb (MTAL), which absorbs HCO3- via apical membrane Na+/H+ exchange. MTAL were perfused in vitro with 25 mM HCO3- solutions (pH 7.4; 290 mosmol/kgH2O). Addition of 0.7 nM NGF to the bath decreased HCO3- absorption from 13.1 +/- 1.1 to 9.6 +/- 0.8 pmol.min-1.mm-1 (P < 0.001). In contrast, with 10(-10) M arginine vasopressin (AVP) in the bath, addition of NGF to the bath increased HCO3- absorption from 8.0 +/- 1.6 to 12.5 +/- 1.3 pmol.min-1.mm-1 (P < 0.01). Both effects of NGF were blocked by genistein, consistent with the involvement of tyrosine kinase pathways. However, the AVP-dependent stimulation required activation of protein kinase C (PKC), whereas the inhibition was PKC independent, indicating that the NGF-induced signaling pathways leading to inhibition and stimulation of HCO3- absorption are distinct. Hypertonicity blocked the inhibition but not the AVP-dependent stimulation, suggesting that hypertonicity and NGF may inhibit HCO3- absorption via a common mechanism. These data demonstrate that NGF inhibits HCO3- absorption in the MTAL under basal conditions but stimulates HCO3- absorption in the presence of AVP, effects that are mediated through distinct signal transduction pathways. They also show that AVP is a critical determinant of the response of the MTAL to growth factor stimulation and suggest that NGF can either inhibit or stimulate apical Na+/H+ exchange activity depending on its interactions with other regulatory factors. Locally produced growth factors such as NGF may play a role in regulating renal tubule HCO3- absorption.
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PMID:Nerve growth factor regulates HCO3- absorption in thick ascending limb: modifying effects of vasopressin. 957 89


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