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)

The present study was designed to test two hypotheses: (1) that angiotensin II (Ang II) stimulates endothelin-1 secretion in cultured rat mesangial cells and (2) that atrial and brain natriuretic peptides (ANP and BNP) inhibit the above-mentioned secretion in these cells. Ang II stimulated immunoreactive (ir) endothelin-1 secretion in a concentration-dependent manner between 10(-8) M and 10(-7) M. The protein kinase C (PKC) inhibitors from two chemical classes, H7 and staurosporine, inhibited secretion following such stimulation. The stimulatory effect of Ang II was also abolished in the PKC-depleted cells. Rat ANP(1-28) and rat BNP-45, which are the respective major circulating forms of ANP and BNP in rats, potently inhibited Ang II-stimulated endothelin-1 secretion in a concentration-dependent manner. Inhibition by ANP and BNP of Ang II-stimulated endothelin-1 secretion was paralleled by an increase in the cellular level of cyclic guanosine 5'-monophosphate (GMP). The addition of a cyclic GMP analogue, 8-bromo cyclic GMP, reduced the stimulated endothelin-1 secretion. Rat ANP(5-25) was less effective that rat ANP(1-28) with respect to inhibiting ir-endothelin-1 secretion and increasing cellular cyclic GMP. These findings indicate that Ang II stimulates endothelin-1 secretion in cultured rat mesangial cells by a mechanism probably involving activation of PKC, and that rat ANP and BNP inhibit this stimulated secretion through a cyclic GMP-dependent process.
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PMID:Angiotensin II stimulates endothelin-1 secretion in cultured rat mesangial cells. 133 47

At least two types of receptors for natriuretic peptides have been reported: biologically active receptors coupled with guanylate cyclase (atrial natriuretic peptide [ANP]-B receptors) and clearance receptors (ANP-C receptors). To elucidate the role of protein kinase C (PKC) in the regulation of ANP-B receptors, vascular smooth muscle cells in culture were treated with phorbol ester. Incubation with receptor agonists and phorbol ester led to the desensitization of receptor-mediated cyclic guanosine monophosphate (ANP-B receptor response) in rat vascular smooth muscle cells. Although a PKC inhibitor and downregulation of PKC by long-term incubation of cells with phorbol esters blocked the phorbol ester-induced desensitization of the ANP-B receptor response, they did not block the ANP-induced desensitization of the ANP-B receptor response. In addition, when desensitization by phorbol esters was observed, ANP was still capable of desensitization. These observations suggest that the mechanism for regulating ANP-B receptor sensitivity may be both PKC-dependent and PKC-independent and mediated by phorbol esters and ANP, respectively.
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PMID:Phorbol ester and atrial natriuretic peptide receptor response on vascular smooth muscle. 134 39

To evaluate an interaction between vasoconstrictive (Ang II) and vasodilating (ANP) peptides, we examined the effect of Ang II on ANP-induced accumulation of cGMP in cultured glomerular mesangial cells. ANP rapidly increased intracellular cGMP levels, with a peak stimulation at one minute in the absence of IBMX and at ten minutes in the presence of IBMX. The ANP-induced cGMP accumulation was significantly inhibited when the cells were treated with Ang II simultaneously with ANP for one minute in the absence of IBMX. This inhibitory effect of Ang II was completely abolished by IBMX and significantly reduced in calcium-free media or by W7, but not affected by H7. Similar inhibitory effect was observed when cells were treated with A23187 but not with TPA for one minute. In the presence of IBMX, Ang II inhibited ANP-induced cGMP accumulation when cells were treated with Ang II for 15 minutes prior to the stimulation by ANP. This inhibition by Ang II was blocked by H7. ANP-induced increase in particulate guanylate cyclase activity was significantly reduced in the cells treated with Ang II or TPA. This reduction of enzyme activity was also prevented by H7. These results indicate that Ang II inhibits ANP-induced cGMP accumulation in cultured glomerular mesangial cells through at least two mechanisms; one is the activation of calcium-dependent, calmodulin-stimulated cyclic nucleotide phosphodiesterase in the initial phase, and the other is the inhibition of guanylate cyclase resulting from protein kinase C activation in the maintenance phase.
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PMID:Dual mechanism of angiotensin II inhibits ANP-induced mesangial cGMP accumulation. 171 65

We studied the effects of two peptides of the endothelin/sarafotoxin family, sarafotoxin-b (SRTX-b) and endothelin (ET-1), as well as the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA) on immunoreactive atrial natriuretic peptide (IR-ANP) release and on haemodynamic parameters (perfusion pressure, heart rate and contractile force) in isolated perfused rat hearts in order to examine the role of intracellular signals in the regulation of ANP secretion. Infusion of SRTX-b at doses of 0.9 and 2.7 nM for 30 min caused a gradual, dose-dependent increase in IR-ANP release and a more rapid coronary vasoconstriction similar to the infusions of ET-1 (2.7 nM) or TPA (46 nM), known to activate protein kinase C in heart cells. A transient inotropic response with a later decrease in contractile force was observed after infusion of each agent. SRTX-b and TPA produced a sustained chronotropic effect, while ET-1 did not significantly affect the heart rate. Infusion of 100 nM of staurosporine, a potent inhibitor of protein kinase C, did not affect basal IR-ANP release into the perfusion fluid but slightly decreased perfusion pressure, heart rate and contractile force. When infused together with SRTX-b, ET-1 or TPA, staurosporine significantly inhibited the ANP secretion, coronary vasoconstriction and changes in cardiac function induced by the peptides or phorbol ester. This study shows that SRTX-b stimulates ANP release with a potency similar to that of ET-1 and that the kinetics of their effects on ANP secretion resemble those of TPA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Staurosporine, a protein kinase C inhibitor, inhibits atrial natriuretic peptide secretion induced by sarafotoxin, endothelin and phorbol ester. 183 Nov 34

The secretory mechanism of rat atrial natriuretic peptide (rANP) was studied in vitro with the use of primary culture of atrial myocytes from neonatal rats. Norepinephrine, phenylephrine, and carbamylcholine stimulated immunoreactive (IR) rANP secretion, whereas neither angiotensin II, arginine vasopressin, nor isoproterenol affected its secretion. The stimulatory effects of carbamylcholine and phenylephrine were blocked by atropine and prazosin, respectively. 12-O-tetradecanoylphorbol-beta-acetate (TPA), protein kinase C activator, induced a dose-dependent increase in IR rANP secretion, and TPA combined with Ca2+ ionophore ionomycin produced a synergistic effect. Ca2+-channel agonist BAY K 8644 also stimulated IR rANP secretion, the effect of which was blocked by Ca2+-channel antagonist nifedipine. These data suggest that alpha 1-adrenergic and muscarinic cholinergic agonists have direct action on rat cardiocytes to stimulate ANP secretion that involves receptor-mediated mobilization of intracellular Ca2+ and activation of protein kinase C.
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PMID:Role of calcium and protein kinase C in ANP secretion by cultured rat cardiocytes. 245 45

The sustained aldosterone secretory response to angiotensin II (ANG II) depends on receptor-mediated increases in membrane diglyceride (DG) and an increase in calcium influx rate. These signals serve to activate membrane-associated protein kinase C (PKC) and result in enhanced phosphorylation of a unique set of proteins. These events can be mimicked by the addition of a phorbol ester, 12-O-tetra decanoyl phorbol 13-acetate (TPA), and a calcium ionophore, A23187, that bypass the initial receptor-associated events. We studied the inhibitory action of atrial natriuretic peptide (4-28 hANP) on the sustained secretory response to ANG II in isolated bovine adrenal glomerulosa cells. Although 10 nM ANP inhibited aldosterone secretion, it did not significantly alter the ANG II-elicited rise in 45Ca2+ influx rate [control (CON): 0.44 +/- 0.06; ANG II: 1.11 +/- 0.12 (P less than 0.001); ANG II + ANP: 1.18 +/- 0.14], the steady-state level of aequorin luminescence [intracellular [Ca2+] ([Ca2+]i)], or the rise in cellular DG content [CON: 0.132 +/- 0.01; ANG II: 0.194 +/- 0.01 (P less than 0.005); ANG II + ANP: 0.202 +/- 0.01 nmol/10(6) cells]. IN addition, ANP was able to inhibit aldosterone secretion stimulated by the combined addition of A23187 + TPA. When protein phosphorylation in the ANP-inhibited cells was evaluated, ANG II-induced protein phosphorylation events were preserved. In contrast to the effect of ANP, the calcium channel blocker nitrendipine abolished the ANG II-induced rise in 45Ca2+ influx rate, reduced the steady-state level of [Ca2+]i, and returned the phosphoproteins to their control states.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of ANP on sustained aldosterone secretion stimulated by angiotensin II. 252 26

Using cultured rat vascular smooth muscle cells (VSMC), the effect of protein kinase C activation on rat atrial natriuretic peptide (rANP) receptors and its effector system was studied. Tetradecanoyl phorbol acetate (TPA) induced a time- and temperature-dependent decrease of 125I-rANP binding to VSMC. TPA and phorbol dibutyrate inhibited the binding in a dose-related manner, whereas biologically inactive beta-phorbol was ineffective. Pretreatment of VSMC with TPA resulted in a marked reduction (50-70%) of rANP binding capacity without a significant change of its binding affinity. TPA pretreatment also induced attenuation of rANP-induced cGMP generation without affecting its basal levels. These data suggest that protein kinase C may be involved in the mechanism of heterologous down-regulation of vascular ANP receptors/guanylate cyclase system.
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PMID:Heterologous down-regulation of vascular atrial natriuretic peptide receptors by phorbol esters. 283 79

Infusion of a phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), known to stimulate protein kinase C, caused a gradual, sustained increase in perfusate immunoreactive atrial natriuretic peptide (IR-ANP) concentration and a more rapid increase in perfusion pressure in the isolated perfused rat heart. Administration of isoprenaline resulted in a rapid rise in IR-ANP release whereas methoxamine induced a sustained increase in IR-ANP secretion into the perfusion fluid. Methoxamine, when infused in combination with TPA, enhanced both IR-ANP secretion and the increase in perfusion pressure produced by phorbol ester. Isoprenaline also acted synergistically on TPA-induced IR-ANP release but attenuated the coronary vasoconstriction produced by phorbol ester. The TPA-induced increase in IR-ANP secretion was attenuated significantly by infusion of atenolol and slightly by infusion of prazosin, neither of which affected TPA-induced vasoconstriction. The vasoconstrictor response to infusion of phorbol ester was similar but the secretory response was attenuated in hearts from rats pretreated with reserpine. The results indicate that adrenoceptor stimulation interacts differentially with phorbol ester-induced ANP secretion and vasoconstriction in the perfused rat heart. Our results also suggest that the effect of TPA on perfusion pressure appears to be due to its direct action on vascular smooth muscle cells but that a part of the TPA effect on ANP secretion may be an indirect one.
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PMID:Adrenergic effect on the atrial natriuretic peptide secretion and vasoconstriction induced in the perfused rat heart by phorbol ester. 289 74

Bovine fasciculata cells in culture (BAC) express both AT1 and AT2 angiotensin receptors. The role and signaling pathways of this latter receptor are still the subject of debate. We found that in BAC stimulation of cortisol (F) production by angiotensin II (A II) is accounted for by both receptor subtypes. We have investigated the potential AT2 signalling pathways involved in this response. As previously described in other cells, we found this receptor to mediate inhibition of ANP stimulated cGMP production through a phosphodiesterase independent pathway. This phenomenon does however not appear to be involved in cortisol production as this response was not affected by the addition of 8-Br-cGMP or ANP. It was however abolished after down-regulation of PKC by phorbol esters, but not by Gi inhibition with pertussis toxin. Moreover and as opposed to the AT1 mediated response, AT2 receptor stimulation potentiated K+ induced F production. In conclusion, these observations suggest that the AT2 pathway which mediates F production requires intact PKC and might involve a Gi independent stimulation of Ca++ or K+ channels.
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PMID:Stimulation of cortisol production through angiotensin AT2 receptors in bovine fasciculata cells. 758 79

Atrial, brain-type, and C-type natriuretic peptides (ANP, BNP, and CNP) act via receptors with intrinsic guanylate cyclase activity. The A-type and B-type ANP receptors are selectively activated by ANP and CNP, respectively. The anterior pituitary is a site of ANP production and action, suggesting a local regulatory function, and this may also hold true for CNP which is found at its highest tissue concentrations in the anterior pituitary. Here we show that these peptides all cause dose-dependent increases in cGMP accumulation in alpha T3-1 cells (a gonadotrope-derived cell line), GH3 cells, and in primary cultures of rat pituitary cells. The response to CNP is particularly robust in alpha T3-1 cells (59 +/- 9-fold increase, EC50 14 +/- 3 nM), and the rank order of potency in alpha T3-1 cells and primary cultures (CNP >> ANP > BNP) is suggestive of action exerted via B-type receptors. Although CNP did not alter GnRH-stimulated LH release or [3H]inositol phosphate accumulation, GnRH reduced CNP-stimulated cGMP accumulation dose dependently (EC50 approximately 0.1 nM). This inhibition reflects the ability of GnRH to shift the CNP dose-response curve rightward (increasing the EC50 for CNP action approximately 10-fold both with and without 3-isobutyl-1-methylxanthine). The inhibitory effect was not blocked by omission of extracellular Ca++ nor mimicked by the Ca++ ionophore A23187 but was mimicked by a protein kinase C (PKC)-activating phorbol ester (which had a comparable effect to GnRH on the EC50 for CNP action). The data imply that CNP rather than (or in addition to) ANP may have a local regulatory function within the pituitary, that although its role is currently unknown it may involve functional interaction with GnRH in gonadotropes, and that the effect of GnRH on CNP action may be PKC-mediated. Moreover, we suggest that alpha T3-1 cells may be a useful model for investigation of the cross-talk between the B-type natriuretic peptide receptor-regulated signal transduction pathway and the Ca++/PKC pathway activated by ligand-stimulated hydrolysis of inositol phospholipids.
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PMID:Cyclic guanosine monophosphate production in the pituitary: stimulation by C-type natriuretic peptide and inhibition by gonadotropin-releasing hormone in alpha T3-1 cells. 768 40


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