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)

Endothelin (ET)-1 and ET-3 induced a biphasic effect (relaxation followed by contraction) in the isolated guinea pig ileum. The contractile but not the relaxant component of the responses was concentration dependent in the dose range studied. Neuronal mechanisms, cyclic guanosine monophosphate (GMP), and adenosine triphosphate (ATP)-dependent K+ channels do not seem to be involved in the relaxing effect of the two isopeptides, since that effect was not affected by either tetrodotoxin, methylene blue, or glibenclamide. Both ET-1 and ET-3 induced tachyphylaxis (homologous desensitization), which was not fully reversed after a 3-h resting period. The responses to both peptides were dependent on the Na+ gradient across the smooth muscle cells, as they were inhibited in low-Na+ medium and after treatment of the preparation with ouabain. Verapamil affected both the relaxant and the contractile components of the responses to the two isopeptides, whereas phorbol-12,13-dibutyrate affected mainly the contractile component. These results suggest that the voltage-operated channels are important for both components of the response induced by ET-1 and ET-3, and that protein kinase C may downregulate Ca2+ signalling. Cross-tachyphylaxis studies between ET-1 and ET-3 suggest the existence of at least two ET receptor subtypes in the guinea pig ileum.
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PMID:Effects of endothelin-1 and endothelin-3 on the isolated guinea pig ileum: role of Na+ ions and endothelin receptor subtypes. 128 81

We investigated the effects of protein kinase C modulations and calcium mobilization on GSH efflux in Hep G2 cells. GSH efflux from Hep G2 cells was increased by a phorbol ester. Staurosporine, an inhibitor of protein kinase C, diminished phorbol ester-stimulated GSH efflux from the cells. GSH efflux was negatively correlated with extracellular calcium concentrations. Verapamil enhanced GSH efflux, whereas ATP decreased GSH efflux. The latter effect was diminished in the absence of extracellular calcium. Protein kinase C and calcium mobilization may be crucial factors in GSH efflux from human hepatocytes.
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PMID:Possible involvement of protein kinase C and calcium in GSH efflux from Hep G2 cells. 133 37

Using fetal brain cells in culture, we have previously shown that activation of the cAMP pathway by forskolin induces the production and secretion of neuropeptide Y (NPY). In this study we wished to ascertain 1) if activation of the protein kinase C pathway induces NPY production and/or secretion and if there is synergism between the pathways, and 2) the role of protein/RNA synthesis and influx of extracellular calcium. Aggregates, formed from dissociated cells obtained from the hypothalamus-olfactory tubercle area of 17-day-old rat fetuses, were cultured in serum-free medium for 12 days. The NPY content of aggregates incubated for 24 h with solvent (control) was 4.4 ng/flask, and the medium content was 7.6 ng. Forskolin (10 microM) or phorbol 12-myristate 13-acetate (PMA; 20 nM) marginally affected aggregate content, but each increased medium content 2- to 3-fold; forskolin and PMA were additive. When cycloheximide (75 microM) was included along with forskolin, PMA, or forskolin plus PMA for a period of 10 h, the increase in NPY medium content was abolished. Actinomycin D (Act-D; 5 micrograms/ml) inhibited the response to each secretagogue in a time-dependent manner. When Act-D was included along with forskolin, PMA, or forskolin plus PMA for a total period of 12 or 24 h, the 12 h increase in content was not affected, whereas the 24 h increase was abolished. When the presence of Act-D was limited to 0-24, 6-24, or 12-24 h, and forskolin plus PMA were included for the entire 24-h period, the increase in NPY content was inhibited by 94%, 57%, and 12%, respectively. Verapamil (100 microM) totally inhibited the 24 h response to forskolin and partially (40-50%) inhibited the response to PMA or forskolin plus PMA. In none of these conditions was the inhibition of the increase in medium NPY content accompanied by an increase in aggregate content, nor was the NPY content of aggregate/medium of control cultures affected.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Forskolin and phorbol ester stimulation of neuropeptide Y (NPY) production and secretion by aggregating fetal brain cells in culture: evidence for regulation of NPY biosynthesis at transcriptional and posttranscriptional levels. 137 Jul 98

1. The relationship between phenylephrine-induced smooth muscle contraction and the subcellular distribution of protein kinase C (PKC) was investigated. 2. Cell shortening induced by phenylephrine (10(-5) M) was measured in single vascular cells freshly isolated from ferret portal vein and aorta. 3. At various time points during phenylephrine activation, single cells were fixed with paraformaldehyde and the distribution of PKC was imaged in cells labelled with the fluorescent PKC probe 12-(1,3,5,7-tetramethylBODIPY-2-propionyl)phorbol-13-acetate. 4. The PKC probe located to a perinuclear region, the cytosol and surface membrane. The amplitude and time course of the phenylephrine-induced changes in the surface membrane/cytosol fluorescence ratio were measured and compared with the amplitude and time course of phenylephrine-induced cell shortening. 5. In portal vein cells incubated in 1 mM-external Ca2+, phenylephrine caused significant shortening and time-dependent translocation of the PKC probe to the surface membrane, but cell shortening preceded PKC translocation. In Ca2+free solution both cell shortening and translocation of the probe were completely inhibited. 6. Verapamil (3 x 10(-7) M) partially, but significantly, inhibited the magnitude of cell shortening and delayed the onset and time to peak shortening. Translocation of PKC in verapamil preceded or coincided with cell shortening. 7. In aorta cells incubated in 1 mM-extracellular Ca2+, phenylephrine induced significant shortening and time-dependent translocation of the PKC probe. Cell shortening preceded PKC translocation. In Ca(2+)-free solution, shortening was only partially, but significantly, inhibited and PKC translocation preceded the fraction of the shortening response that remained. 8. These data are consistent with a role for PKC in the maintenance of the phenylephrine-induced contraction in both portal vein and aorta. The data also suggest that phenylephrine-induced contraction may involve activation of a Ca(2+)-dependent PKC isoform in ferret portal vein but a Ca(2+)-independent isoform in ferret aorta.
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PMID:Phenylephrine-induced translocation of protein kinase C and shortening of two types of vascular cells of the ferret. 148 63

Previously, we demonstrated that removal of fetal bovine serum (FBS) from the medium of human skin fibroblasts resulted in an accelerated 86Rb+ washout, decreased cellular K+, and increased Na+ contents. In the present study we examined the mechanism underlying these changes. The efflux rate constant for 86Rb+, and the cellular contents of Na+ and K+ were measured. Verapamil (K1/2 = 15 microM) and chlorpromazine (K1/2 = 1 microM) reduced by approximately 70% the increased 86Rb+ washout evoked by FBS removal. The effect of the two drugs was additive at low, but not high, concentrations. Verapamil and chlorpromazine also attenuated the decrease in cellular K+ content and prevented the increase in cellular Na+ content associated with FBS depletion. Bumetanide (50 microM) was only partially effective in offsetting the enhanced 86Rb+ efflux and was completely without any effect on the cellular Na+ and K+ changes induced by FBS removal. In the presence of FBS, A-23187 produced a slight and transient increase of the 86Rb+ washout. The protein kinase C activator phorbol 12-myristate 13-acetate enhanced the 86Rb+ efflux in FBS-containing medium for a prolonged period but this increase was only a fraction of that caused by serum removal. Cellular Na+ and K+ contents were not changed by the phorbol ester. We conclude that FBS removal raises the cellular Na+ content, and enhances 86Rb+ efflux, through a calmodulin-dependent pathway activated by calcium influx.
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PMID:Characterization of Na(+)-K+ homeostasis of cultured human skin fibroblasts in the presence and absence of fetal bovine serum. 157 13

We have examined the effect of phorbol myristate acetate (PMA) on airway smooth muscle (ASM) in the presence and absence of respiratory epithelium (RE) and analyzed the dependence of this response on extracellular sodium, Na+/H+ exchange, calcium, and cyclooxygenase products; we determined both the resting membrane potential and isometric force developed by ASM preparations. Removal of RE had no effect on the values of the resting membrane potential of ASM cells. In the presence of RE in the preparation, both electrical and contractile responses to PMA (10(-5) M) were significantly different compared with the response of ASM to PMA without RE. When the RE was present, stimulation of protein kinase C caused only a biphasic response in both membrane potential and isometric force. In either the presence or absence of RE, amiloride (10(-5) M) and a low-sodium solution inhibited both electrical and contractile changes of ASM cells caused by PMA. In the presence or absence of RE, verapamil (10(-5) M) attenuated (P less than 0.05) both electrical and contractile responses of ASM cells as induced by PMA. Verapamil, however, had no effect on the last phase of PMA-induced response. Pretreatment of preparations with indomethacin (10(-6) M) changed the PMA-induced response of ASM with RE to a response usually observed in ASM without RE. Finally, the incubation of tracheal preparations without RE with prostaglandin E2 (10(-8) M) altered the response of these preparations in such a way that their electrical and contractile response to PMA was essentially identical to the PMA response observed in preparations with an intact RE.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Respiratory epithelium-dependent inhibition of protein kinase C of airway smooth muscle cells. 186 96

The involvement of the calcium messenger system in the control of steroidogenesis in the rat and bovine adrenal cortex has been studied extensively. However the role of these second messengers in the control of human adrenocortical function is not established. This was therefore studied by incubating collagenase-dispersed human adrenocortical cells with the calcium ionophore A23187 and the protein kinase C activator phorbol 12-myristate 13-acetate (TPA). The effects of the calcium channel blocker verapamil on basal and stimulated steroidogenesis were also studied. Both TPA (1 pmol/l-10 mumol/l) and A23187 (1 nmol/l-10 mumol/l) caused a dose-dependent increase in cortisol, aldosterone and corticosterone production. Verapamil (10 mumol/l) inhibited the increase in aldosterone, corticosterone and cortisol produced in response to ACTH(1-24), potassium, and desacetyl-alpha MSH. Unlike previous results in the rat, these effects were not specific for aldosterone secretion. The results suggest that, as in other species, calcium mobilization and protein kinase C activation have a role in the control of steroidogenesis in the human adrenal cortex. However, in contrast to the rat, these mechanisms appear to be involved in the control of steroidogenesis in both the zona glomerulosa and inner zone cells.
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PMID:Control of steroidogenesis by the calcium messenger system in human adrenocortical cells. 201 56

Using a cloned murine cell line, NKB61A2, that concomitantly exhibits both NK and natural cytotoxic (NC) activities, we investigated the biochemical mechanisms involved in natural cell mediated cytotoxicity against NK-sensitive YAC-1 tumor cells and against the NC-sensitive WEHI-164 tumor cells. Recent reports have suggested that target cell lysis by cytotoxic lymphocytes occurs by either a calcium dependent and/or a calcium-independent mechanism(s). To determine the role of calcium in NK and NC activities of the NKB61A2 cell line, we evaluated the effect of: 1) extracellular Ca2+ depletion by the divalent cation chelator, EGTA, 2) Ca2+ influx blockade by the Ca2+ channel blocker verapamil, and 3) blocking of intracellular Ca2+ mobilization by 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester (TMB-8). We found that EGTA, verapamil, and TMB-8 were all capable of inhibiting NK activity, but they had little effect on NC activity of the NKB61A2 cells. Using 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide which are inhibitors of protein kinase C and calmodulin respectively, we determined that protein kinase C and calmodulin do play a role in the NK activity of NKB61A2 cells. 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine and N-(6-aminohexyl)-5-chloro-1-naphthalanesulfonamide, similar to Verapamil and TMB-8, had no effect on NC activity. Thus, the data indicate that the NK activity of NKB61A2 cells is calcium dependent whereas NC activity is not. These results may explain the disparate reports seen in the literature of calcium-dependent and -independent lysis of tumor cells.
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PMID:Calcium-dependent natural killer and calcium-independent natural cytotoxic activities in an IL-2-dependent killer cell line. 212 Mar 46

Recent observations suggest that a phospholipid-sensitive, calcium-dependent protein kinase affects the contractile responses of vascular smooth muscle. Protein kinase C activators such as the tumor-promoting phorbol esters have been used as tools to study protein kinase C function in various intact cells. The present study characterizes vascular reactivity to protein kinase C activation in rats made hypertensive by coarctation of the abdominal aorta. Thoracic aortic strips from hypertensive rats developed greater force than arteries from normotensive rats in response to the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA). Thoracic aortae from hypertensive rats were more responsive (lower threshold dose) to the phorbol ester than those from normotensive rats. Additionally, arteries from hypertensive rats were more responsive to the contractile effects of mezerein, a non-phorbol ester activator of protein kinase C. Removal of the endothelium did not eliminate the difference in responsiveness to TPA in thoracic aortae from normotensive and hypertensive rats. The threshold dose of TPA in abdominal aortae from hypertensive rats was not different from that in normotensive rats. However, the maximal response to 10(-6) mol/l TPA after 60 min in abdominal aortae from hypertensive rats was significantly less than that in aortae from normotensive rats. Thus, contractile responses to TPA appear to be influenced by arterial pressure per se. The inhibitory effects of the calcium antagonist, verapamil, in thoracic aortae from hypertensive rats were greater than in those from normotensive rats. Verapamil inhibited TPA-induced contractions in abdominal aortae from hypertensive rats to the same extent as in those from normotensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vascular responsiveness to phorbol esters in coarctation-hypertensive rats. 216 84

Indirect evidence indicates that parathyroid hormone (PTH) interacts with pancreatic islets and modulates their insulin secretion. This property of PTH has been implicated in the genesis of impaired insulin release in chronic renal failure. We examined the direct effect of PTH-(1-84) and PTH-(1-34) on insulin release using in vitro static incubation and dynamic perifusion of pancreatic islets from normal rats. Both moieties of the hormone stimulated in a dose-dependent manner glucose-induced insulin release but higher doses inhibited glucose-induced insulin release. This action of PTH was modulated by the calcium concentration in the media. The stimulatory effect of PTH was abolished by its inactivation and blocked by its antagonist [Tyr-34]bPTH-(7-34)NH2. PTH also augmented phorbol ester (TPA)-induced insulin release, stimulated adenosine 3',5'-cyclic monophosphate (cAMP) generation by pancreatic islets, and significantly increased (+50 +/- 2.7%, P less than 0.01) their cytosolic calcium. Verapamil inhibited the stimulatory effect of PTH on insulin release. The data show that 1) pancreatic islets are a PTH target and may have PTH receptors, 2) stimulation of glucose-induced insulin release by PTH is mediated by a rise in cytosolic calcium, 3) stimulation of cAMP production by PTH and a potential indirect activation of protein kinase C by PTH may also contribute to the stimulatory effect on glucose-induced insulin release, and 4) this action of PTH requires calcium in incubation or perifusion media.
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PMID:Direct effect of parathyroid hormone on insulin secretion from pancreatic islets. 219 36


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