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)

Tannin, a polydisperse polyphenol extracted from cotton bracts (CBE), has been implicated in the pathogenesis of byssinosis, a lung disease of mill workers. CBE tannin inhibits chloride secretion in airway epithelial cells by means of an unknown mechanism(s). Activation of protein kinase C (PKC) by PMA (phorbol 12-myristate 13-acetate) in airway cells increases chloride secretion. The effect of tannin on this PKC pathway was examined, using canine tracheal epithelium mounted in Ussing chambers. PMA addition (10 nM) to the mucosal bath resulted in a 0.36 +/- 0.07 microEq/cm2.h (mean +/- SEM, n = 20) increase in short-circuit current (Isc) and a 0.38 +/- 0.17 microEq/cm2.h increase in net chloride secretion (Jnet). The inactive 4 alpha-phorbol had no effect. Tannin addition to the mucosal bath produced a dose-dependent decrease in Isc and Jnet. In tissues pretreated with 2-50 micrograms/ml tannin, and subsequently stimulated with PMA, tannin inhibited PMA stimulation of chloride secretion beginning at a tannin concentration of 10 micrograms/ml (0.09 +/- 0.05 microEq/cm2.h [n = 10] increase in Isc and 0.08 +/- 0.03 microEq/cm2.h increase in Jnet with PMA after tannin pretreatment). At 50 micrograms/ml tannin, the stimulatory effect of PMA was completely abolished. The known PKC inhibitor, H-7 (20 microM), inhibited PMA stimulation, while chelerythrine (2 microM) had not effect on PMA-stimulated Isc and Jnet, and calphostin C was toxic to the airway epithelium. In membrane fragments, 2.5 micrograms/ml tannin inhibited the rate of histone III phosphorylation by PMA from 32.1 +/- 4.4 nmol/mg protein per min to 20.1 +/- 2.7 nmol/mg protein per min (n = 7). In bovine airway cells, tannin pretreatment (2.5 micrograms/ml) decreased the cytosolic activity of PKC but had no effect on PKC translocation to the membrane. We conclude that tannin inhibits chloride secretion in airway epithelial cells in part by inhibiting PKC.
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PMID:Tannin inhibition of protein kinase C in airway epithelium. 756 89

Previous studies have shown that stimulus-secretion coupling for the release of insulin from the pancreatic islet is potentiated by phospholipase A2 activity. Several biochemically distinct phospholipase A2 activities have been described in the islet. A recently identified cytosolic high molecular weight phospholipase A2, which requires Ca2+ for association with cellular membranes but not for catalytic activity can be activated in a protein kinase C-dependent manner in other cell-types. We determined its phosphorylation and activation in response to phorbol ester and glucose in cultured islet cells from neonatal rats. Islet cell monolayers were labelled to equilibrium with [32P]orthophosphate. Following stimulation cytosolic phospholipase A2 was immunoprecipitated and, after electrophoretic separation and transfer to nitrocellulose membrane, 32P-labelled protein was detected by autoradiography. Phospholipase A2 activity of islet cell cytosol was determined by hydrolysis of exogenous I-stearyl- 2[14C]arachidonyl phosphatidylcholine substrate. It could be shown that phosphorylation of immunoprecipitated phospholipase A2 was augmented by prolonged glucose exposure (> 1 hr) in a protein kinase C-dependent manner. Phosphorylation occurred concomitant with a glucose-induced increase in total cellular phospholipase A2 activity (177 +/- 3 nmol substrate hydrolysed/mg protein at glucose 5.6 mM vs 267 +/- 32 (SEM, n = 4) at glucose 25 mM, P < 0.05). Both acute protein kinase C (459 +/- 71) and glucose-activated phospholipase A2 activities were reduced in the presence of a specific arachidonic acid analogue inhibitor of cytosolic phospholipase A2 (to 231 +/- 10 and 161 +/- 17, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Glucose-induced phosphorylation and activation of a high molecular weight cytosolic phospholipase A2 in neonatal rat pancreatic islets. 758 5

To examine the interaction of protein kinase C (PKC) with agonist-induced calcium fluxes in hypertension, cytosolic free calcium ([Ca2+]i) was measured in vascular smooth muscle cells (vSMC) of normotensive and spontaneously hypertensive rats (SHR) after incubation with phorbol,-12 myristate,-13 acetate (PMA) and application of angiotensin II (AII). To distinguish between calcium influx through voltage-dependent calcium channels and calcium mobilization from intracellular stores, the calcium agonist BayK 8644 was used. Resting [Ca2+]i was 108.0 +/- 10.6 nM (mean +/- SEM, n = 25) in normotensive and 102.0 +/- 11.4 nM (n = 21) in hypertensive cells. After pretreatment with PMA 10(-7) M for 60 min, resting [Ca2+]i of normotensive vSMC increased to 145.0 +/- 13.8 nM (n = 17) while the resting level of the hypertensive cells decreased to 68.0 +/- 2.4 nM (n = 14, p < 0.05 as compared with normotensive cells) in hypertensive vSMC. Maximum increase in [Ca2+]i induced with 10 M AII for normotensive and hypertensive vSMC was similar: 230.5 +/- 34.4 nM (n = 14) and 212.5 +/- 26.7 nM (n = 17). After pretreatment with PMA 10(-7) M, the maximum increase in [Ca2+]i induced by AII in hypertensive cells was limited to 108.0 +/- 6.2 nM (p < 0.05 as compared with normotensive cells), whereas the increase in [Ca2+]i in normotensive vSMC remained the same as before: 211.5 +/- 23.4 nM. After administration of 10(-5) M BayK 8644, [Ca2+]i increased by 54.3 +/- 12.2 nM (n = 4) and 43.4 +/- 17.4 nM (n = 5) in normotensive and hypertensive vSMC, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Angiotensin II responses after protein kinase C activation in vascular smooth muscle cells of spontaneously hypertensive rats. 768 44

Sixteen dogs were entered into a study of the double subarachnoid hemorrhage (SAH) model of cerebral vasospasm. Six animals were sacrificed 72 hours after the first experimental SAH, and the remaining 10 animals were killed 72 hours after the second experimental SAH; ten additional animals served as controls. Basilar arteries were rapidly excised from the dogs and frozen. Multiple segments of the frozen arteries were analyzed independently for total protein and 1,2-diacylglycerol (DAG) content, which averaged 3.17 (+/- 0.27 standard error of the mean; SEM) pmol DAG/microgram protein for all 25 arteries analyzed. A slight decreasing trend in DAG content relative to that of control vessels was found in vessels chronically constricted in situ by subarachnoid blood clot; however, this trend did not attain statistical significance. Two segments of the same vessels were assayed independently for protein kinase C (PKC) activity, which averaged 1.21 (+/- 0.08 SEM) pmol phosphate incorporation per minute per microgram protein for all 24 arteries analyzed. A small decrease in PKC content was noted in vessels that experienced a single SAH; however, PKC returned to near control value in vessels subjected to double SAH. The ratio of particulate (membrane bound) to soluble PKC activity, an indicator of PKC translocation to the membrane and hence PKC activation, showed a small but statistically significant trend to increase with experimental SAH.
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PMID:Protein kinase C and diacylglycerol content in basilar arteries during experimental cerebral vasospasm in the dog. 771 10

Cirrhotic livers are considered to regenerate less actively than normal livers after hepatic resection. Little is known about the mechanisms responsible for impaired capacity of regeneration in cirrhotic liver. In the present study, we investigated the effect of phorbol ester on hepatocyte proliferation in healthy and cirrhotic hepatocytes, using one of the phorbol esters, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), which has a direct effect on activation of protein kinase C (PKC). Cirrhosis was established by the administration of carbon tetrachloride and phenobarbital to rats. Healthy and cirrhotic hepatocytes were isolated from Wistar male rats by a two-step collagenase perfusion technique. DNA synthesis was estimated by [3H]thymidine incorporation into DNA and by autoradiographic nuclear labeling index. [3H]Thymidine incorporation was measured 24 hr after hepatocytes were stimulated by appropriate reagents. TPA (50 nM) stimulated [3H]thymidine incorporation in healthy hepatocytes (control vs TPA, 991 +/- 247 vs 2569 +/- 766 mean +/- SEM cpm/microgram DNA; P < 0.05), whereas TPA (50 nM) failed to stimulate in cirrhotic hepatocytes (control vs TPA, 1144 +/- 184 vs 1304 +/- 187 cpm/microgram DNA; NS). Staurosporine, a specific PKC inhibitor, suppressed [3H]thymidine incorporation in TPA-stimulated healthy hepatocytes (806 +/- 263 cpm/microgram DNA; P < 0.05); however, it had no effect on cirrhotic hepatocytes (1295 +/- 180 cpm/microgram DNA; NS). An autoradiographic nuclear labeling index exhibited the same results with [3H]thymidine incorporation. We conclude that TPA stimulates hepatocyte proliferation in healthy rat hepatocytes but has no effect on cirrhotic hepatocytes.
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PMID:Impaired phorbol ester-induced hepatocyte proliferation in cirrhosis. 772 25

The possible regulation of adenosine 3',5'-cyclic monophosphate (cAMP) accumulation by arachidonic acid (AA) was studied in segments, microdissected from the rat kidney, which are sensitive to arginine vasopressin (AVP). In the presence of 5 microM indomethacin, the addition of 5 microM AA did not impair AVP-dependent cAMP accumulation (measured during 4 min at 35 degrees C) in the cortical or outer medullary collecting tubule, but decreased this response in the thick ascending limb with an inhibition much more pronounced in the medullary portion (MTAL) than in the cortical portion. In MTAL, the response to 10 nM AVP was inhibited by 34.4 +/- 9.6% (SEM) and 65.8 +/- 5.4% with 1 microM and 5 microM AA, respectively, N = 5 experiments. AVP-, glucagon- and calcitonin-sensitive cAMP levels in MTAL were inhibited by 5 microM AA to a similar extent. AA-induced inhibition was unaffected by the presence of inhibitors of AA metabolism: (1) either 10 microM indomethacin or 50 microM ibuprofen added to all media; (2) a 10-min pre-incubation and a 4-min incubation of MTAL samples with 10 microM eicosa-5,8,11,14-tetrayonic acid, (3) a 1-h preincubation with either 30 microM SKF-525A, 20 microM ketoconazole, or 20 microM nordihydroguariaretic acid. In contrast to AA, 11 other saturated or unsaturated fatty acids had no inhibitory effect on the AVP-dependent cAMP level. In fura-2-loaded MTAL samples, AA induced a slow increase of the intracellular calcium concentration ([Ca2+]i) which reached 21.0 +/- 3.8 nM and 92.9 +/- 21.4 nM over basal values (n = 11) at 2 min and 4 min, respectively, after the beginning of the superfusion of 5 microM AA. AA-induced inhibition of AVP-dependent cAMP accumulation was due neither to the increase in [Ca2+]i elicited by AA, nor to an activation of protein kinase C because this inhibition: (1) was not blocked when MTAL samples were incubated either in zero Ca2+ medium, or in the presence of 1,2-bis(2-aminophenoxy)ethane-N, N, N', N'-tetraacetic acid (BAPTA) to chelate [Ca2+]i, and (2) it was not reproduced by a pre-treatment of MTAL segments with a phorbol ester. Pre-incubation of MTAL (6 h at 35 degrees C) with 500 ng/ml pertussis toxin (PTX) prevented AA-induced inhibition: in the presence of PTX inhibition was 24.7 +/- 6.6% vs 10 nM AVP, as compared to 81.6 +/- 4.0% in control groups, i.e in the absence of PTX, N = 6.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Arachidonic acid inhibits hormone-stimulated cAMP accumulation in the medullary thick ascending limb of the rat kidney by a mechanism sensitive to pertussis toxin. 779 41

Previous studies have demonstrated that prostaglandin E2 (PGE2) inhibits arginine vasopressin-(AVP)dependent adenosine 3',5'-cyclic monophosphate (cAMP) accumulation in microdissected rat outer medullary collecting tubules (OMCD), by a mechanism unrelated to the inhibition of cAMP synthesis. The potential role of the activation of protein kinase C (PKC) to explain the negative regulation elicited by PGE2 was investigated in this study. Single OMCD samples were pre-incubated (10 min, 30 degrees C) in the presence or absence of either activators of PKC, phorbol 12-myristate 13-acetate (PMA), 1-oleoyl-2-acetyl-glycerol (OAG), dioctanoylglycerol (DOG) or an inhibitor of PKC, staurosporine (SSP). These compounds were present also with the agonists tested during the incubation period (4 min, 35 degrees C). In contrast to PGE2, activators of PKC did not decrease AVP-dependent cAMP accumulation (mean +/- SEM): 1 nM AVP = 47.1 +/- 6.8 fmol.mm-1 x 4 min-1; AVP+0.3 microM PGE2 = 20.1 +/- 2.7, P < 0.01 versus AVP; AVP + 10 nM PMA = 42.0 +/- 4.7, NS versus AVP; AVP + 50 micrograms/ml OAG = 44.1 +/- 4.8. NS versus AVP, N = 5 experiments. However, 10 nM PMA prevented PGE2-induced inhibition: AVP + PGE2 = 44.2 +/- 3.5% of the response to AVP and 90.3 +/- 3.2% without and with PMA respectively, N = 16. Similar results were obtained with either 50 micrograms/ml OAG or 25 micrograms/ml DOG (AVP + PGE2 + OAG = 92.9 +/- 6.6% of the response to AVP, N = 8; AVP + PGE2 + DOG = 94.1 +/- 5.3%, N = 7).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The activation of protein kinase C prevents PGE2-induced inhibition of AVP-dependent cAMP accumulation in the rat outer medullary collecting tubule. 790 84

The transient outward current (ITO) is an important repolarizing component of the cardiac action potential. In native cardiac myocytes, ITO is modulated after activation of protein kinase C, although the molecular nature of this effect is not well understood. A channel recently cloned from human ventricular myocardium (Kv1.4, HK1) produces a rapidly inactivating K+ current, which has phenotypic similarities to the 4-aminopyridine-sensitive component of ITO. Therefore, we examined whether this recombinant channel was also modulated by protein kinase C activation by investigating the effects of the diacylglycerol analogue phorbol 12-myristate 13-acetate (PMA) on Kv1.4 K+ current expressed in Xenopus oocytes. At a concentration of 10 nmol/L, PMA caused a biphasic response with an initial increase (14 +/- 4%, mean +/- SEM) in current, which peaked in 14 minutes. This was followed by a significant reduction (40 +/- 11%) in the current within 30 minutes. There was no significant change in cell membrane electrical capacitance with 10 nmol/L PMA (1 +/- 1% decline in 30 minutes), demonstrating that loss of cell membrane surface area did not explain the reduction in K+ current, although cell capacitance did decrease when using a higher concentration of PMA (81 nmol/L). The inactive stereoisomer, 4 alpha-PMA, had no effect on Kv1.4 current, whereas preincubation with the protein kinase inhibitor staurosporine or protein kinase C-selective chelerythrine prevented the effects of PMA. When purified from a stably transfected mammalian cell line by using immunoprecipitation, the channel protein was readily phosphorylated in vitro by purified protein kinase C.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of an inactivating human cardiac K+ channel by protein kinase C. 795 54

Transient K+ outward currents (Ito) were measured in enzymatically isolated ventricular mouse heart cells with a patch clamp technique in the whole cell configuration. Exposure of the cells to substrate-free anoxia gradually decreased both the peak and the late Ito. The inactivation time course of Ito was fitted with two exponentials. After 4-10 min of anoxia, the contribution of the fast and slow exponential decreased to 60 +/- 7% and 62 +/- 4% of the control value and recovered after reoxygenation within 1-3 min to 84 +/- 5% and 75 +/- 6% (n = 10; all mean +/- SEM), respectively. The time constants of the exponentials were invariant to anoxia. Voltage dependence of activation and inactivation of Ito were not influenced by anoxia. Application of stimulators of protein kinase A and C, cGMP- dependent protein kinase, or of the oxidant diamide during anoxia did not recover Ito. It is concluded that under conditions of metabolic stress, Ito is reversibly down-regulated leaving inactivation kinetics unchanged. The underlying mechanism is as yet unknown but does neither involve a decreased activity of protein kinase A, protein kinase C, nor c-GMP dependent protein kinase.
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PMID:Anoxia decreases the transient K+ outward current in isolated ventricular heart cells of the mouse. 797 Nov 53

The effects of alcohol exposure on human peripheral circulating lymphocyte protein kinase C (PKC) activity were characterized in lymphocytes harvested from two sample groups. The first group (control) consisted of 30 nonalcoholic male subjects and the second group consisted of nine male subjects with chronic alcoholism. Alcoholic subjects were admitted for detoxification to a substance abuse unit located in a nonprofit community hospital. In this group of subjects, blood was sampled on admission for detoxification (pre-A), and after 5 days (post-A). Subjects received chlordiazepoxide for treatment of alcohol withdrawal symptoms. PKC activities measured in the control, pre-A, and post-A groups expressed as pmol/microgram/min +/- SEM were 5.09 +/- 0.50, 1.81 +/- 0.43, and 3.95 +/- 0.44. Control PKC was significantly higher than pre-A PKC (p < or = 0.05) and post-A PKC was significantly higher than pre-A PKC (p < or = 0.05). Total lymphocyte PKC activity was also found to be inversely related to age, expressed by the relationship log(PKC) = 0.870-0.005(Age), with R = 0.433.
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PMID:Effects of chronic alcohol use and age on human lymphocyte protein kinase C activity. 797 7


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