Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A critical problem in determining the intracellular mechanisms regulating atrial natriuretic peptide (ANP) secretion is the extrapolation of data obtained in cultures of atrial myocytes isolated from neonatal animals to that obtained in intact atria isolated from adult animals. We have therefore examined ANP secretory responses in primary cultures of atrial myocytes isolated from adult rats to more closely approach the adult phenotype. Activation of alpha 1-adrenergic receptors by norepinephrine (in the presence of propranolol) increased the rate of ANP secretion approximately two-fold (EC50 = 0.32 microM). This response was mediated predominantly by the alpha 1A-like subtype of alpha 1-receptors. Phorbol esters increased the rate of ANP secretion approximately 2.4-fold independently of alpha 1-receptor occupancy. Kinetic analysis showed that the secretory responses to either agonist did not appear to diminish within 2 h. The responses to both alpha 1-adrenergic stimulation and phorbol ester addition were inhibited by the protein kinase C inhibitor, H-7, but not by structurally related isoquinolines. Influx of extracellular Ca2+, independently of its effects on contraction of the myocytes, was also necessary for a full secretory response to alpha 1-receptor activation. Additionally, the secretory response to alpha 1-adrenergic agonists was attenuated by calmodulin inhibitors. In contrast to the response to alpha 1-adrenergic receptor activation, stimulation of beta-adrenergic receptors or addition of a membrane permeable cAMP analog reduced the rate of both basal and alpha 1-stimulated ANP secretion. These results show that activation of alpha 1-adrenergic receptors in adult rat atrial myocytes directly increases the rate of ANP secretion. This response is dependent upon protein kinase C and supported by extracellular Ca2+ influx. Conversely, activation of beta-adrenergic receptors, which increases intracellular cAMP, directly inhibits ANP secretion.
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PMID:Regulation of atrial natriuretic peptide secretion by alpha 1-adrenergic receptors: the role of different second messenger pathways. 802 22

The respective roles of protein kinase C (PKC) and endogenous prostaglandin formation in angiotensin II (Ang II)-induced myocardial secretion of atrial natriuretic peptide (ANP) was studied in cultured, spontaneously beating, neonatal-rat cardiomyocytes. Incubation of cardiomyocytes with 0.1 microM Ang II led to a rapid but transient increase in particulate-bound PKC activity, a response accompanied by marked increases in cellular 6-oxo-prostaglandin F1 alpha (6-oxo-PGF1 alpha) generation and ANP secretion. A role for PKC in Ang II-induced 6-oxo-PGF1 alpha formation and ANP secretion was apparent, insofar as both responses were suppressed in the presence of the PKC inhibitors staurosporine (1 microM) and CGP 41251 (1 microM), as well as in cells in which PKC had been previously down-regulated by pretreatment with phorbol diester. Furthermore, Ang II-induced 6-oxo-PGF1 alpha production was found to be strongly correlated with Ang II-induced ANP release (r = 0.87, P < 0.001, n = 6), indicating a role for prostacyclin (PGI2) in Ang II-induced ANP secretion in these cells. This hypothesis was confirmed by finding that both Ang II-induced 6-oxo-PGF1 alpha production and ANP release were abolished in the presence of the respective phospholipase A2 and cyclo-oxygenase inhibitors quinacrine (10 microM) and indomethacin (10 microM), whereas exogenously applied PGI2 (1 microM) and prostaglandin E2 (0.1 microM) mimicked Ang II-induced ANP secretion in this system. Taken together, these results suggest that Ang II induces ANP secretion in spontaneously beating rat cardiomyocytes via a PKC-dependent autocrine pathway involving a cyclo-oxygenase product and a yet-to-be-identified myocardial prostanoid receptor.
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PMID:Protein kinase C-dependent prostaglandin production mediates angiotensin II-induced atrial-natriuretic peptide release. 813 55

Exposure of cultured, spontaneously beating rat cardiomyocytes to arginine vasopressin (AVP) led to marked increases in the release of prostacyclin (PGI2) and atrial natriuretic peptide (ANP). These responses were accompanied by a rapid, transient rise of cytosolic free Ca2+ concentration ([Ca2+]i) and of membranous protein kinase C (PKC) activity. Ca2+ influx and PKC activity appeared to play important but distinct roles in AVP-induced cellular responses, insofar as only AVP-induced ANP secretion was abolished by the Ca2+ channel antagonist nifedipine, whereas both AVP-induced PGI2 production and ANP release were abolished by the PKC inhibitors staurosporine and CGP-41251. The AVP-induced increase in [Ca2+]i could also be mimicked with the vasopressin (V1-subtype) agonist Octapressin, but not with the V2-agonist 1-desamino-8-D-arginine vasopressin, and was fully abolished by the V1-antagonist [d(CH2)5Tyr(Me)]AVP, but not by d(CH2)5-D-Leu-VAVP (V1-/V2-antagonist). These results indicate that V1-vasopressinergic receptors mediate AVP-induced PGI2 production and ANP secretion in rat cardiomyocytes and that, whereas both Ca2+ influx and PKC activation are required for AVP-induced ANP secretion, AVP-induced PGI2 formation is mainly regulated by PKC.
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PMID:[Ca2+]i and protein kinase C in vasopressin-induced prostacyclin and ANP release in rat cardiomyocytes. 814 61

Primary cultures of neonatal rat atrial myocytes were subjected to down-regulation of protein kinase C (PKC) and to inhibition of PKC activity. The effects on secretion of atrial natriuretic peptide (ANP), and the intracellular distribution of ANP-containing specific granules and their association to microtubules, were investigated. Treating the cultures with inhibitors of PKC, staurosporine or H7, a translocation of ANP-containing specific granules from the perinuclear sarcoplasm to the periphery of the myocytes was observed, and furthermore, secretion of ANP was significantly decreased. The microtubule network were not structurally affected by the PKC inhibitors. Down-regulation of PKC by 12-O-tetradecanoylphorbol 13-acetate (TPA) for 12 h was not followed by any alteration of localization of specific granules, and the amount of secreted ANP was still considerable. Treating the down-regulated cultures with staurosporine, secretion of ANP was still significantly reduced. The present results suggest that the decreased ANP secretion and the translocation of ANP-containing specific granules in the atrial myocytes following treatment with staurosporine or H7, is mediated through mechanisms not, or only partly, requiring PKC.
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PMID:Inhibition and down-regulation of protein kinase C in cultured atrial myocytes: effects on distribution of specific granules and secretion of atrial natriuretic peptide. 822 21

The effect of shear stress on the release of endothelin-1 (ET-1) from endothelial cells is at present controversial with various investigators observing an increase and others observing a decrease. Our data reveal that the release of ET-1 from primary cultures of human umbilical vein endothelial cells varies with the duration and the level of shear. Sustained exposure to low levels of shear (1.8 dyn/cm2) or a brief exposure (< 1 h) to 10 dyn/cm2 caused a sustained stimulation of ET-1 release. Staurosporine (STPN) completely blocked the stimulation in both cases, suggesting that ET-1 release is increased via activation of protein kinase C (PKC). Exposure to 6-25 dyn/cm2 for > or = 6 h dramatically inhibited ET-1 release and led to 0-70% inhibition of cumulative release by 16 h. Pretreatment with N omega-nitro-L-arginine (L-NNA) reversed this suppression in a dose-dependent manner, implicating either nitric oxide (NO) and/or guanosine 3',5'-cyclic monophosphate (cGMP) as a requirement for shear-mediated inhibition of ET-1 release. Treatment of stationary cultures with 8-bromo-cGMP and atrial natriuretic peptide mimicked the inhibition of ET-1 release caused by shear and revealed that cGMP is capable of inhibiting ET-1. Likewise, the inhibitory effects of shear were potentiated and diminished by 3-isobutyl-1-methylxanthine (IBMX) and methylene blue, respectively. Thus cGMP also appears to exert an inhibitory effect in cells exposed to shear.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Shear stress regulates endothelin-1 release via protein kinase C and cGMP in cultured endothelial cells. 838 8

Parathyroid hormone-related protein (PTHrP), a tumor product responsible for malignancy-associated hypercalcemia, is also produced in many normal tissues, including vascular smooth muscle cells (SMC). As PTHrP exhibits vasodilatory properties, we postulated that other vasoactive agents may control PTHrP gene expression in SMC. Addition of angiotensin II to serum-deprived SMC resulted in a marked induction of PTHrP mRNA by 2 h, with a peak (6-10-fold) at 4-6 h. Angiotensin II effects on PTHrP gene expression were inhibited by saralasin, an angiotensin II receptor antagonist, and blocked by actinomycin D and cycloheximide, suggesting a requirement for gene transcription and protein synthesis. Nuclear run-off assays revealed a 3-fold increase in PTHrP gene transcription 1 h after angiotensin II treatment. Angiotensin II also prolonged PTHrP mRNA half-life by 2-3-fold. Angiotensin-induced PTHrP mRNA is partially dependent on cyclooxygenase products and protein kinase C activation. Other vasoconstrictor substances, including serotonin and bradykinin, also stimulated PTHrP expression, whereas the vasodilator atrial natriuretic peptide did not. Addition of recombinant PTHrP-(1-141) significantly inhibited angiotensin II-induced SMC DNA synthesis. PTHrP expression is increased by angiotensin II through transcriptional and post-transcriptional mechanisms. In addition, PTHrP modulates the effect of angiotensin II on SMC proliferation. This suggests that PTHrP acts locally in SMC, possibly to oppose the vasoactive and/or growth-promoting effects of vasoconstrictor agents such as angiotensin II.
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PMID:Angiotensin II regulates parathyroid hormone-related protein expression in cultured rat aortic smooth muscle cells through transcriptional and post-transcriptional mechanisms. 842 Sep 73

This study presents an investigation of the mechanism of angiotensin II (Ang II)-induced atrial natriuretic peptide (ANP) release in superfused sliced right atria of rats. Ang II (0.1 microM) enhanced ANP release by 49%. This phenomenon was significantly blocked by (Sara1-Ileu 8) Ang II (1 microM) and losartan (0.1 microM). The use of neomycin (100 microM), a phospholipase-C inhibitor completely suppressed the effect of Ang II on ANP increase. To elucidate the intracellular mechanism of ANP released by Ang II, the role of protein kinase C (PKC) was determined by 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7) and phorbol ester : 4-beta-phorbol 12-myristate-13-acetate (PMA). We observed that PMA (0.1 microM) stimulated ANP release whereas H-7 (10 microM), an inhibitor of PKC in the presence of Ang II, prevented ANP increase. The role of calcium was also evaluated with 8-(N-N-diethylamino)-ocytyl-3,4,5, trimethoxy-benzoate (TMB-8) (10 microM) and N-(6-aminohexyl)-5-chloro-1-naphtalene sulfonamide (W-7) (10 microM), which completely inhibited ANP release by Ang II. Pre-treatment with diltiazem (10 microM), an antagonist of the Ca++ channel, did not prevent ANP increase due to Ang II, but A23187 (5 microM) enhanced ANP release by Ang II. These results suggest that PKC and intracellular calcium play an important role in ANP release under the influence of Ang II in rat atrial tissue.
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PMID:Cellular mechanism of angiotensin II-induced atrial natriuretic peptide release in rat right atrial tissue. 863 99

We determined previously that astroglia cultured from newborn rat brain contain both guanylyl cyclase-coupled and atrial natriuretic peptide (ANP)-C natriuretic peptide receptors. Here, we investigated the effects of the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) on these receptor subtypes in cultured astroglia to understand the intracellular processes involved in the modulation of natriuretic peptide receptors in these cells. PMA (10 nM to 1 microM; 15 min to 24 h) treatment elicited a time- and concentration-dependent decrease in the numbers of 125I-labeled ANP specific binding sites, which was inhibited by the PKC antagonist staurosporine (500 nM). Furthermore, PMA (100 nM, 2 or 24 h) treatment elicited a significant decrease in the specific binding of 125I-des-Cys-Cys-ANP, an ANP-C receptor selective ligand. PMA (10 nM to 1 microM; 30 min) treatment also significantly decreased ANP (100 nM)-stimulated guanosine 3', 5'-cyclic monophosphate levels in cultured astroglia, an effect unmodified by phosphodiesterase inhibition. These data indicate that PKC modulates both guanylyl cyclase-coupled and ANP-C natriuretic peptide receptors in cultured astroglia.
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PMID:Protein kinase C modulates natriuretic peptide receptors in astroglial cultures from rat brain. 863 52

How 4 beta-phorbol 12-myristate 13-acetate (PMA) and ionomycin (Io), a calcium ionophore, affect on the atrial natriuretic peptide (ANP) stimulated cyclic-3',5'-guanosine monophosphate (cGMP) production in cultured rat mesangial cells was examined. Cultured mesangial cells were prepared by isolated glomeruli from Sprague Dawley rats employing the sieving method and were used between the 3rd and 15th passage for experiments. cGMP and protein contents were measured by radioimmunoassay and Lowry method. Incubations with effectors were carried out either in the presence or absence of 0.5 mM 1-methyl-3-isobutyl-xanthine (MIX). The intracellular concentration of calcium ([Ca2+]i) was determined by using the Fura-2 method. Pretreatment with PMA, an activator of protein kinase C (PKC), attenuated ANP stimulated cGMP production in a time- and dose-dependent fashion, while alpha PDD (an inactive analog of PMA) did not inhibit cGMP production. PMA inhibition was reversed by addition of staurosporine, a protein kinase C inhibitor. Io attenuated ANP stimulated cGMP production in the absence but not in the presence of MIX. These findings suggested that PMA acts on ANP receptor or guanylate cyclase via activation of PKC in rat mesangial cells. Io may inhibit ANP stimulated cGMP production via activation of cyclic nucleotide phosphodiesterase.
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PMID:PMA and ionomycin differently affect atrial natriuretic peptide stimulated cyclic GMP production in rat mesangial cells. 872 95

The new functional role of corticotropin-releasing factor (CRF) in the regulation of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) release was investigated using cultured neonatal rat cardiomyocytes. Treatment with CRF (10(-10)-10(-6) M) resulted in dose- and time-dependent increase in ANP and BNP secretion, up to 2.5-fold and 1.8-fold above control values, respectively. The effect was significant at 6 hr and persisted for at least 36 hr. The effect of CRF (10(-7) M) was partially blocked by alpha-helical CRF(9-41) (10(-7) M), a specific CRF receptor antagonist. The effect of CRF (10(-7) M) was not only blunted by cAMP-dependent protein kinase A (PKA) inhibitor, H-89 (10(-5) M), but also by protein kinase C inhibitors, H-7 (50 microM) and Calphostin C (10(-6) M). H-7 (50 microM) and Calphostin C (10(-6) M) alone lowered basal ANP and BNP levels. Furthermore, CRF (10(-7) M) stimulates protein synthesis up to 1.2-fold. These results indicate that CRF stimulates ANP and BNP secretions through the CRF receptor and, at least in part, via PKA activation during cardiac hypertrophy.
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PMID:Stimulation by corticotropin-releasing factor of atrial natriuretic peptide and brain natriuretic peptide secretions from cultured neonatal rat cardiomyocytes. 875 66


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