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)

Airway mucosa consists of several types of cells including ciliated cells, mucus secreting cells, basal cells and Clara cells. In this review, fine structures of these epithelial cells and intercellular junctions are demonstrated by scanning and transmission electron microscopy, and the proposed kinetics of cellular maturation and development are discussed. Airway epithelium not only plays a role as a mechanical barrier at the air-surface interface but also possesses a wide variety of functions. Ciliary beating has been recognized to be one of the important determinants for mucociliary transport by clearing inhaled particles and bacteria from the airway. We found that the motility of cilia can be regulated by intracellular second messengers, such as Ca2+, cAMP, and protein kinase C. When ciliated epithelium is encountered by physicochemical stimuli, these signal transduction systems are activated through phosphatidylinositol turnover and/or Ca2+ channel opening, which subsequently modulate the synthesis of ATP, an energy source of ciliary beating. Airway epithelium contains the enzyme neutral endopeptidase which can degrade several peptides into inactive fragments, thus regulating the actions of tachykinins released from sensory C-fibers via axon reflex. Ion transport across airway mucosa is determined by Cl secretion and Na absorption in airway epithelium. To elucidate the mechanism of airway hypersecretion under several conditions of respiratory diseases, the effects of chemical mediators, neuropeptides, and inflammatory mediators on electrical properties of canine cultured tracheal epithelium were studied. We also expanded this idea to human subjects and found that indomethacin inhalation was valuable in reducing the amounts of sputum production by inhibiting Cl and water secretion into the airway lumen. In addition, airway epithelium can modulate contraction of airway smooth muscle by generating epithelium-derived relaxing factor (EpDRF). We have shown that lipopolysaccharide-induced airway hyperreactivity seems attributable to the loss of airway epithelium with EpDRF.
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PMID:[Structure and function of airway epithelial cells]. 207 99

Postreceptor protein stimulation significantly alters the transport state of the ex vivo small intestine. This study investigated the effects of neural blockade on basal and stimulated ionic transport. Rabbit ileal segments (n = 46) were arterially perfused with an oxygenated sanguinous buffered electrolyte solution. The lumen was perfused with an isotonic solution containing [14C]polyethylene glycol as a nonabsorbable marker. Net fluxes of H2O, Na+, and Cl- were calculated. Tetrodotoxin (TTX) was used to block enteric neural transmission. Forskolin (FOR) was used to activate adenylate cyclase, and phorbol 12,13-dibutyrate (PDB) served to activate protein kinase C. Two groups were studied. Group A preparations had no TTX pretreatment, while group B preparations were pretreated with TTX. In the Group A preparations, TTX at 10(-6) M and PDB at 10(-5) M caused significant proabsorptive effects with a delta FH2O of +20 +/- 7 and +15 +/- 2 microliters/min, respectively (P less than 0.05), while FOR stimulated significant secretion with a delta FH2O of -14 +/- 3 microliter/min (P less than 0.05). In the Group B TTX-pretreated preparations, FOR did not cause secretion and PDB maintained an absorptive state. These results indicate that neural blockade with TTX reverses basal secretion in the ex vivo intestine, suggesting that an intact enteric nervous system maintains the secretory status of the intestine. FOR-induced adenylate cyclase-activated secretion does not occur in the presence of TTX, implying that intact neural transmission is required for the FOR effect. PDB-induced protein kinase C-activated absorption occurs despite neural blockade, suggesting that the PDB-induced proabsorptive effect is mediated without neural intermediaries.
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PMID:Neural blockade in basal and postreceptor-stimulated intestinal transport. 216 69

Previous studies using phorbol esters and cell-free preparations suggest that protein kinase C (PKC) may regulate Cl- secretion and apical membrane Cl- channels in airway epithelium. To determine whether PKC may be involved in receptor-mediated control of secretion, we measured the mass of diacylglycerol (DAG) generated by two Cl- secretagogues, isoproterenol and bradykinin. Bradykinin increased cellular DAG at concentrations similar to those that increase inositol phosphates, suggesting that bradykinin stimulates phosphatidylinositol hydrolysis, as observed in other systems. Isoproterenol also increased cellular DAG at concentrations similar to those that stimulate adenosine 3',5'-cyclic monophosphate (cAMP) accumulation. The beta-adrenergic receptor antagonist, nadolol, blocked and cell-permanent analogues of cAMP mimicked the effect of isoproterenol. However, isoproterenol does not stimulate phosphatidylinositol turnover. Simultaneous addition of maximal concentrations of isoproterenol and bradykinin produced additive increases in DAG. To test the possibility that the isoproterenol-induced increase in DAG came from phosphatidylcholine turnover, we measured the release of water-soluble choline metabolites and the incorporation of choline into cellular lipids. Although phorbol ester and bradykinin stimulated phosphatidylcholine turnover, isoproterenol did not. These results suggest that isoproterenol and bradykinin generate DAG from the following different lipid sources: bradykinin stimulates phosphatidylinositol hydrolysis to produce DAG; isoproterenol stimulates an increase in DAG from unknown sources. The data suggest that simultaneous activation of cAMP-dependent protein kinase and PKC may occur during receptor-mediated stimulation of Cl- secretion.
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PMID:Isoproterenol, cAMP, and bradykinin stimulate diacylglycerol production in airway epithelium. 216 9

It is well known that prostaglandin E2 (PGE2) both inhibits arginine vasopressin (AVP)-stimulated water permeability (hydraulic conductivity, Lp) in the cortical collecting duct (CCD) or, if administered alone, modestly increases Lp in the CCD. These bifunctional effects on Lp correspond to PGE2's capacity to inhibit AVP-stimulated adenylate cyclase (AC) activity, or to singularly stimulate AC activity in the collecting duct. The present studies suggest that the inhibitory effect of PGE2 on Lp may also be mediated by phosphatidylinositol (PI) hydrolysis. Using in vitro microperfused rabbit CCDs, we show that PGE2 releases Ca from intracellular stores. We also demonstrate that the inhibitory effect of PGE2 on AVP-stimulated Lp in the CCD is significantly reversed by the protein kinase C (PKC) inhibitor, staurosporine (SSP). Although PGE2 does not reduce an established water flow response to 8-(4-chlorophenylthio)-adenosine 3',5'-cyclic monophosphate (8-CPTcAMP), when the sequence of addition is reversed and PGE2 is added first, marked inhibition of 8-CPTcAMP-induced Lp is observed. This provides independent evidence that PGE2 can act through a mechanism separate from modulating AC activity. PGE2 inhibition of 8-CPTcAMP-induced Lp is reversed by SSP pretreatment. Finally, SSP pretreatment also markedly potentiates the capacity of PGE2 itself to increase Lp. We conclude that PGE2 releases Ca from intracellular stores and, by activating PKC, inhibits AVP-induced osmotic water flow. This suggests an important role for PI hydrolysis in mediating PGE2's effects on the CCD.
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PMID:PGE2 inhibits AVP-induced water flow in cortical collecting ducts by protein kinase C activation. 216 17

Despite advances in the knowledge of the intracellular signalling in response to extracellular messengers, the mechanism of action of interleukin-1 (IL-1) has remained an enigma. In the present study, we have employed human dermal fibroblasts (Detroit 532 cells) to investigate IL-1 beta-induced changes in intracellular signals. Both recombinant human IL-1 beta and a native preparation purified from human placental tissue were employed. Cyclic AMP levels in cell monolayers were unaltered by IL-1 beta. Also, IL-1 beta did not influence significantly the levels of phosphatidylinositol, phosphatidylinositol 4-monophosphate, and phosphatidylinositol 4,5-bisphosphate in the membrane, nor the water-soluble inositol phosphates, inositol monophosphate, inositol bisphosphate and inositol trisphosphate, in cells prelabelled with myo-[3H]inositol. In addition, intracellular calcium as measured by Quin2 was unaffected by interleukin-1. However, in cells labelled with [3H]glycerol or [3H]arachidonic acid, IL-1 beta caused an immediate rise in diglyceride (DG) accumulation. As the effects of IL-1 beta have been reported to be mimicked by tumour-promoting phorbol esters, this rise in DG suggested the involvement of protein kinase C (PKC). However, repeated experiments failed to reveal any acute effect of IL-1 beta on the activity of this enzyme. Furthermore, IL-1 beta did not cause the translocation of PKC between the membrane and the cytosol as has been found in response to other extracellular signals. Rather, IL-1 beta appeared to increase the synthesis of PKC in both membrane and cytosol preparations, an effect which could be prevented by coincubation with cycloheximide. These findings suggest that the diglyceride formed in response to IL-1 beta does not activate protein kinase C.
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PMID:Interleukin-1 stimulates diglyceride accumulation in the absence of protein kinase C activation. 217 Oct 43

In the present study we have examined the action of the phorbol diester tetradecanoyl phorbol acetate, an activator of protein kinase C, on the transepithelial transport of sodium, chloride and water and the production of cAMP in the isolated frog skin epithelium (Rana esculenta). Addition of tetradecanoyl phorbol acetate to the mucosal solution resulted initially in an increase in the short-circuit current, which was followed by a progressive decrease. If the short-circuit current was first activated by addition of the antidiuretic hormone, arginine vasotocin, then the addition of tetradecanoyl phorbol acetate resulted only in a pronounced inhibition. The changes in the short-circuit current were the result of changes in the active influx of Na+. The effect of tetradecanoyl phorbol acetate on the intracellular potential measured under short-circuited conditions (Vscc) was time-dependent. Just after addition of tetradecanoyl phorbol acetate to the mucosal solution, Vscc depolarized; this was followed by a slight hyperpolarization, after which Vscc continued to decline. The inhibition of the Na+ transport by tetradecanoyl phorbol acetate was associated with a decline in the response to the antidiuretic hormone (arginine vasotocin), but the ability of arginine vasotocin to increase the cellular level of cAMP and to stimulate the osmotic water flow was not affected by the presence of tetradecanoyl phorbol acetate. In skin halves in which the short-circuit current was stimulated with arginine vasotocin, addition of tetradecanoyl phorbol acetate resulted in a dose-dependent inhibition of the short-circuit current, but only minor changes in Vscc were observed. The results presented suggest that the addition of tetradecanoyl phorbol acetate to the isolated frog skin first increases and then decreases the arginine vasotocin-sensitive sodium permeability of the apical membrane. This might be due to a stimulating effect of tetradecanoyl phorbol acetate on both the activation and deactivation (turnover) of the sodium channels.
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PMID:Effect of 12-O-tetradecanoyl phorbol 13-acetate on solute transport and production of cAMP in isolated frog skin. 217 32

Recently, phospholipase D-mediated hydrolysis of phosphatidylethanolamine (PtdEtn) was shown to be stimulated by activators of protein kinase C (Kiss, Z., and Anderson, W. B. (1989) J. Biol. Chem. 264, 1483-1487), suggesting that PtdEtn metabolism may play a role in signal transduction. Here we have studied the possible regulation of PtdEtn hydrolysis by adenine and guanine nucleotides, as well as by sphingosine, both in membranes isolated from [14C]ethanolamine- or [32P]PtdEtn-prelabeled NIH 3T3 cells and in intact cells. In isolated membranes both ATP and ADP stimulated the hydrolysis of PtdEtn. Both nucleotides had maximal (approximately 2-fold) effects at about 0.5 mM concentration. The main water-soluble product of [14C]PtdEtn hydrolysis was [14C]ethanolamine, while in [32P] PtdEtn-prelabeled membranes the nucleotides stimulated the formation of [32P]phosphatidic acid, suggesting the involvement of a phospholipase D-type enzyme. The hydrolysis-resistant analogs of GTP, such as guanosine 5'-3-O-(thio)triphosphate and guanyl-5'-yl imidodiphosphate, greatly potentiated the stimulatory effects of ATP and ADP on PtdEtn hydrolysis. On the other hand, the nonphosphorylating analogs of ATP, adenyl-5'-yl beta,gamma-imidodiphosphate and beta,gamma-methyl-eneadenosine 5'-triphosphate, failed to stimulate PtdEtn hydrolysis both in the absence and presence of guanosine triphosphates. Sphingosine, while exhibiting no effect alone, had a relatively modest (1.2-1.3-fold) potentiating effect on ATP-stimulated PtdEtn hydrolysis in isolated membranes. The effect of sphingosine was mimicked by threo- and erythrosphinganines, while N-acetylsphingosine was without effect. In studies with [14C]ethanolamine-prelabeled intact NIH 3T3 cells, externally added ATP did not stimulate PtdEtn hydrolysis. In contrast, sphingosine and sphinganines had much greater stimulatory effects on PtdEtn hydrolysis in intact cells than with isolated membranes. These data indicate that PtdEtn hydrolysis may be regulated by adenine and guanine nucleotides in addition to, or in cooperation with, the activators of protein kinase C, and that sphingosine may be an additional regulator of PtdEtn hydrolysis.
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PMID:ATP stimulates the hydrolysis of phosphatidylethanolamine in NIH 3T3 cells. Potentiating effects of guanosine triphosphates and sphingosine. 218 45

The hypothesis that placental secretion of progesterone (P4) and ovine placental lactogen (oPL) are controlled through different mechanisms was tested. Placental tissue was obtained at days 133-138 of pregnancy, and explant incubations were established using 200 mg tissue per flask in 5 ml O2-saturated DMEM containing 24 mM HEPES and lacking phenol red (pH 7.4). Following a 30-min preincubation, and a 15-min control period, test substances were added and incubations continued, with periodic gassing, for 4 h at 37 degrees C in a shaking water bath. Dopamine (DA), norepinephrine (NE) and epinephrine significantly stimulated P4 production (P less than 0.05). The enhancement of placental P4 production was mimicked by the addition of 8-bromo-cyclic adenosine monophosphate and forskolin (P less than 0.05). The response to catecholamines was abolished by the addition of propranolol (P less than 0.05) but not by phentolamine (P greater than 0.05). Inclusion of a membrane-permeant substrate for P4 synthesis, 25-hydroxycholesterol, increased basal (P less than 0.05) but did not enhance agonist-induced P4 production (P greater than 0.05). High performance liquid chromatographic analysis of placental tissue demonstrated the presence of DA (80.8 +/- 7.07 pg/mg) and NE (48.8 +/- 5.77 pg/mg), as well as catecholamine metabolites. Addition of 1,2-dioctanoyl-sn-glycerol (DAG) or phorbol 12-myristate-13-acetate (PMA) enhanced oPL secretion (P less than 0.05) without affecting P4 production. The response to DAG and PMA, representing the release of considerably more oPL than can be detected by extracting the tissue, was not influenced by treatment with cycloheximide (P greater than 0.05) indicating that secretion of preformed oPL is regulated by the protein kinase C pathway. These results support the hypothesis that the secretion of oPL and the production of P4 are controlled by different mechanisms.
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PMID:Differential control of placental lactogen release and progesterone production by ovine placental tissue in vitro. 223 15

Using in vivo microperfusion in the proximal convoluted tubule (PCT) of the Munich-Wistar rat, we investigated the impact of varying protein kinase C (PKC) activity on the rate of bicarbonate reabsorption and on its regulation by angiotensin II. Activation of PKC with luminal perfusion of phorbol 12-myristate 13-acetate (PMA, 5 x 10(-7) M) caused bicarbonate absorption in the S1 PCT to increase by 25%, from 346 +/- 7 to 432 +/- 4 peq.mm-1.min-1 (P less than 0.001), without affecting intracellular cAMP level. Another PKC stimulator, dioctanoylglycerol, had the same effect. Inhibition of PKC activity with luminal perfusion of 5 x 10(-6) M sphingosine had the opposite effect, decreasing bicarbonate absorption by 45% to 190 +/- 2 peq.mm-1.min-1 (P less than 0.001). Pretreatment with PMA or with sphingosine each attenuated by approximately one-third the bicarbonate absorptive response usually observed following angiotensin II administration. Similar results for the action of PKC, but of smaller magnitude, were found in the S2 PCT. In conclusion, activation of PKC increases bicarbonate and water absorption in the S1 and S2 PCT in vivo, and PKC may participate in as much as one-third of the transport stimulation induced by angiotensin II.
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PMID:Role of protein kinase C in proximal bicarbonate absorption and angiotensin signaling. 233 Sep 86

The role of protein kinases in renal noradrenergic stimulation was examined using sphingosine, 1-(5-isoquinolinylsulfonyl)-2-methyl-piperizine (H7), using sphingosine, 1-(5-isoquinolinylsulfonyl)-2-methyl-piperizine (H7), or staurosporine to inhibit the responses to norepinephrine (NE, 60 nM) in isolated perfused rat kidneys. Sphingosine (20 mumol/L) increased the noradrenergic vasoconstrictor response. H7 (10 mumol/L) partially blocked the immediate vasoconstrictor response and completely inhibited it after 2 min without altering the antinatriuretic and antilithuretic responses. H7 also blocked the increase in free water produced by NE, which is consistent with the inhibition of protein kinase A linked to beta-adrenergic stimulation. Staurosporine (10 nmol/L) partially inhibited noradrenergic vasoconstriction and antinatriuresis, and it completely blocked the depression of gluconeogenic responses to NE in pyruvate-perfused kidneys. To examine the role of diacylglycerol and protein kinase C in the renal responses to NE, we used oleoyl-acetyl-glycerol (OAG, 50-100 microM) or phorbol-12-myristyl-13-acetate (TPA, 5-50 nM). TPA slowly vasoconstricted the kidney and reduced GFR and fractional Na+, Li+, and free water excretion. Amiloride (1 mM) prevented the TPA responses. OAG mimicked the effects of TPA except that vasoconstriction occurred more rapidly and was brief. Both TPA and OAG acted like alpha 1-adrenergic agonists. These results indicate that diaclyglycerol and protein kinase are involved in the prolonged effects of NE on vasoconstriction. GFR, and proximal tubular reabsorption.
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PMID:Diacylglycerol and protein kinase mediated noradrenergic responses in perfused rat kidneys. 239 Jul 42


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