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)

The mechanism of inhibition of HCO3 transport by parathyroid hormone (PTH) in the proximal tubule is not clearly defined. Previous studies in vitro have suggested that this effect is mediated via cAMP generation, which acts to inhibit Na/H exchange, resulting in cell acidification. To examine this question in vivo, intracellular pH (pHi) was measured in the superficial proximal tubule of the rat using the pH-sensitive fluoroprobes 4-methylumbelliferone (4MU) and 2',7'-bis(carboxyethyl)-(5, and 6)-carboxyfluorescein (BCECF). PTH was found to alkalinize the cell. This alkalinization suggested inhibition of basolateral base exit, which was confirmed by in situ microperfusion studies: lowering HCO3 in peritubular capillaries acidified the cell, an effect blunted by PTH. Removal of luminal Na promoted basolateral base entry, alkalinizing the cell. This response was also blunted by PTH. Readdition of luminal Na stimulated the luminal Na/H exchanger, causing an alkalinization overshoot that was partially inhibited by PTH. cAMP inhibited luminal H secretion but did not alkalinize the cell. Stimulation of phosphatidylinositol-bis-phosphate turnover by PTH was suggested by the effect to the hormone to increase cell Ca. Blocking the PTH-induced rise in cell Ca blunted the effect of the hormone to alkalinize the cell, as did inhibition of phosphatidylinositol breakdown. Furthermore, stimulation of protein kinase C by a phorbol ester and a diacylglycerol applied basolaterally alkalinized the cell and inhibited luminal H secretion. The findings indicate that both arms of the phosphatidylinositol-bis-phosphate cascade play a role in mediating the effect of PTH on the cell pH. The results are consistent with the view that PTH inhibits base exit in the proximal tubule by activation of the phosphatidylinositol cascade. The resulting alkalinization may contribute, with cAMP, to inhibit apical Na/H exchange and the PTH-induced depression of proximal HCO3 reabsorption.
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PMID:Parathyroid hormone decreases HCO3 reabsorption in the rat proximal tubule by stimulating phosphatidylinositol metabolism and inhibiting base exit. 131 50

The ability of cyclic AMP (cAMP) to modulate human B cell proliferative responses and the possible role of cAMP-dependent kinases (PKA) in cAMP modulation of proliferative responses were investigated. The addition of dibutyl cAMP (Bt2 cAMP) or the cAMP-elevating agent forskolin to B cells stimulated by crosslinking surface immunoglobulins (sIg) resulted in a concentration-dependent inhibition of proliferative responses. By contrast, Bt2 cAMP or forskolin enhanced the proliferative responses of B cells after direct stimulation by phorbol myristate acetate (PMA) and the calcium ionophore ionomycin. The inhibition and enhancement of B cell proliferative responses by Bt2 cAMP were observed at different incubation intervals and were not due to temporal shifts of optimal responses. Also, Bt2 cAMP caused only small changes in B cell RNA synthesis compared to modulation of proliferative responses. Exposure of B cells to Bt2 cAMP rapidly activated PKA. Blocking Bt2 cAMP activation of PKA with the kinase inhibitor HA1004 prevented Bt2 cAMP enhancement of B cell responses after direct stimulation by PMA and ionomycin. In reciprocal experiments, the kinase inhibitor H7 resulted in some inhibition of PKC activation but did not inhibit Bt2 cAMP activation of PKA or Bt2 cAMP enhancement of proliferative responses. Other experiments demonstrated that B cells treated with Bt2 cAMP had selective increases in the de novo phosphorylations of two endogenous substrates which reflected PKA activation. Furthermore, concentrations of HA1004 or H8 which inhibited Bt2 cAMP enhancement of proliferative responses also inhibited PKA phosphorylations of these substrates whereas H7 did not. Thus, elevations of cAMP can enhance or inhibit human B cell proliferative responses to different stimuli and the activation of PKA is important for cAMP enhancement of certain responses.
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PMID:Cyclic AMP modulation of human B cell proliferative responses: role of cAMP-dependent protein kinases in enhancing B cell responses to phorbol diesters and ionomycin. 132 Apr 64

Anti-lymphocyte and anti-thymocyte globulins (ATG) are currently used as immunosuppressive agents in organ transplantation. Their administration in vivo may induce not only lymphocyte depletion but also functional effects which were investigated in the present study. In vitro ATG inhibited T-cell proliferation induced by monocyte-dependent T-cell mitogens, like CD3 antibodies, phytohaemagglutinin (PHA) and concanavalin A (Con A), by monocyte-independent mitogens, like CD2 antibodies, or by protein kinase C activators (phorbol esters) associated with a calcium ionophore. The inhibitory effect of ATG was therefore not solely accounted for by a suppression of co-stimulatory signals delivered by monocytes, but rather implied a direct action on T cells. Addition of recombinant human interleukin-2 (rIL-2) did not overcome the inhibition. Suppression of T-cell proliferation by ATG was characterized by normal RNA synthesis and IL-2 secretion contrasting with markedly reduced expression of the CD25 protein [p55, the alpha-chain of interleukin-2 receptor (IL-2R)] both in cytoplasm and on T-cell membrane, as well as a decreased secretion of interferon-gamma (IFN-gamma). Northern blot analysis revealed increased levels of CD25 and IFN-gamma mRNA, suggesting a post-transcriptional inhibition of these molecules, whereas IL-2 mRNA levels were unchanged. These data demonstrate that inhibition of T-cell proliferation by ATG can be attributed primarily to a post-transcriptional defect of CD25 expression, implying a novel mechanism different from those described with other immunosuppressive agents. Blocking of T-cell proliferation in the late G1 phase of the cell cycle may contribute to the immunosuppressive activity of ATG in prophylactic treatment of allograft rejection.
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PMID:Inhibition of CD25 (IL-2R alpha) expression and T-cell proliferation by polyclonal anti-thymocyte globulins. 139 65

The regulation of intracellular pH (pHi) and its role in the insulin-secretory process were evaluated, by using the clonal insulin-secreting cell line RINm5F. Glyceraldehyde, lactate and dihydroxyacetone decreased pHi, but only the first two released insulin. In the presence of extracellular Na+ the cells counteracted the acidification. Blocking the Na+/H+ exchange in acidic cells resulted in a drastic further lowering of pHi, an effect not obtained under basal conditions. Whereas glyceraldehyde depolarized the cells, lactate was without effect. Dihydroxyacetone hyperpolarized the cells in the presence of extracellular Na+, but this effect disappeared when Na+ was excluded from the medium. Stimulation with glyceraldehyde resulted in increased free cytoplasmic Ca2+ concentration ([Ca2+]i). Dihydroxyacetone and lactate had no effect on [Ca2+]i in the presence of Na+, but lactate induced a decrease in [Ca2+]i in Na(+)-deficient medium. In RINm5F cells the activity of the Na+/H+ antiport could not be augmented by activation of protein kinase C (PKC). Hence, in insulin-secreting cells a PKC-insensitive Na+/H+ antiport is the major mechanism restoring a decrease in pHi. Acidification itself does not affect membrane potential, but may directly interact with the mechanisms regulating exocytosis.
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PMID:Intracellular pH and the stimulus-secretion coupling in insulin-producing RINm5F cells. 141 91

Activators of protein kinase C (PKC) stimulate Na+ transport (JNa) across frog skin. We have examined the effect of Ca2+ on PKC stimulation of JNa. Both the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) and the diacyl-glycerol sn-1,2-dioctanoylglycerol (DiC8) were used as PKC activators. Blocking Ca2+ entry into the cytosol (either from external or internal stores) reduced the subsequent natriferic effect of the PKC activators. This negative interaction did not simply reflect saturation of activation of the apical Na+ channels, since the stimulations produced by blocking Ca2+ entry and adding cyclic AMP were simply additive. The Ca2+ dependence of the natriferic effect could have reflected either a direct action of cytosolic Ca2+ on PKC or an indirect action on the final receptor site (the Na+ channel). To distinguish between these possibilities, the TPA- and phospholipid-dependent kinase activity of broken-cell preparations was assayed. The kinase activity was not stimulated by physiological levels of Ca2+, and in fact was inhibited at millimolar concentrations of Ca2+. We conclude that the effects of Ca2+ on the natriferic response to PKC activators are indirect. Reducing cytosolic uptake of Ca2+ may have stimulated Na+ transport by a chemical modification of the apical channels observed in other tight epithelia. The usual stimulation of Na+ transport produced by PKC activators in frog skin may reflect the operation of a nonconventional form of PKC. This enzyme is Ca2+ independent and seems related to the nPKC or PKC epsilon observed in other systems.
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PMID:Ca(2+)-independent form of protein kinase C may regulate Na+ transport across frog skin. 164 90

In bullfrog sympathetic ganglion cells, muscarine produced an inward current (Imus) through the activation of a subtype (M1) of muscarinic acetylcholine receptor (mAChR) by suppressing an outward M-current (IM), and/or activating cation-selective current (ID; see below). The former was induced with a potency (Kd = 0.5 microM) higher than the latter (Kd = 5 microM) before and after blocking a fraction of the receptor with an irreversible blocker. Activators of protein kinase C mimicked muscarine's actions. Blocking IM by Ba2+ increased ID. These results suggest that activation of M1-mAChR both closes M-channel and opens cation-selective D-channel through phosphoinositide breakdown and the subsequent activation of protein kinase C and that a difference in potency at the last step of the cascade determines the order in which channels are regulated.
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PMID:Regulation of two ion channels by a common muscarinic receptor-transduction system in a vertebrate neuron. 244 24

Induction of ornithine decarboxylase (ODC, E.C. 4.1.1.17) activity by parathyroid hormone (PTH) in cultured fetal rat osteoblasts was studied. PTH induced ODC activity and stimulated cAMP production in a dose-dependent manner, the ED50 for cAMP being five times as high as that for ODC. Induction of ODC activity by PTH was partly inhibited by actinomycin D and cycloheximide, with 40 and 55% inhibition, respectively. PTH increased the intracellular ionized calcium concentration ([Ca2+]i), which was absent in a Ca2+-free medium. Blocking calcium influx, lowering the extracellular calcium concentration, and adding trifluoperazine inhibited both induction of ODC activity and stimulation of cAMP production by PTH. A23187 (100 nM and 1 microM), combined with a low dose of PTH (4 nM), resulted in a synergistic induction of ODC activity and an inhibition of cAMP production. A23187 inhibited induction of ODC activity as well as stimulation of cAMP production by the dose of PTH (20 nM) maximally effective in inducing ODC activity. Forskolin together with this maximal dose of PTH resulted in an additive effect on ODC activity and a synergistic stimulation of cAMP production. The current results show similarities and differences with respect to results obtained with osteoblasts from other species and osteoblast cell lines. The present data indicate that (1) PTH stimulates ODC activity and this is partly due to new enzyme synthesis; (2) calcium is involved in induction of ODC activity and stimulation of cAMP production by PTH; furthermore, it is suggestive that calmodulin and/or protein kinase C are involved; and (3) stimulation of cAMP production by PTH depends on an optimal intracellular calcium concentration range.
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PMID:Parathyroid hormone-induced ornithine decarboxylase activity in fetal rat osteoblasts. 255 85

Peculiarities of pharmacological and metabolic sensitivities of delayed potassium outward current depending on extracellular calcium ions (IK(Ca(out)) have been studied in experiments on isolated intracellularly perfused Helix neurons. It is shown that verapamil depresses the amplitude and accelerates the inactivation of this current. Blocking effect of verapamil increases with extracellular Ca2+ concentration. Functioning of IK(Ca(out)) channels depends on the intracellular metabolic processes. The current amplitude decreases during the neuron perfusion. Lowering of the intracellular solution temperature to +10 degrees C brings about the analogous result. Addition of ATP (2 mmol/l) and Mg2+ (3 mmol/l) to the intracellular perfusate prevents a decrease of potassium current; intracellular introduction of the exogenous protein kinase C restores the amplitude of this current. Polymyxin B (10(-4) mol/l), a blocker of protein kinase C, depresses the potassium current sensitive to extracellular calcium ions. The possible mechanism of Ca2+ action on IK(Ca(out)) through phosphatidyl-inositol metabolism is discussed.
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PMID:[Pharmacologic and metabolic dependence of the delayed inactivated potassium outward current in the somatic membrane of snail neurons]. 272 85

The 10B4 system of human T cells seems to constitute a member of T cell receptor complex. We have analyzed the mechanisms by which a monoclonal antibody against the 10B4 molecule activates human peripheral T cells. The 10B4 antibody together with goat anti-mouse immunoglobulin antibody induced significant increase of DNA and RNA syntheses in T cells with peak responses on day 9 and on day 7, respectively. This activation process is mediated by interleukin 2 (IL-2) and its receptor (IL-2R), because (1) IL-2 activity was detected in the culture supernatants, (2) the percentage of IL-2R positive cells increased during the culture period, with a peak on day 9, and (3) the 10B4-induced T cell proliferation was inhibited by anti IL-2R antibody. Blocking studies with pharmacological agents showed that in the 10B4-induced system, a protein kinase C (PK-C) inhibitor, palmitoylcarnitine, blocked DNA synthesis, RNA synthesis, IL-2 production and IL-2R expression whereas a Ca ion channel blocker, verapamil, inhibited DNA synthesis, RNA synthesis, IL-2 production but not IL-2R expression. It is thus concluded that PK-C activation is required for IL-2 production and IL-2R expression and that channel-mediated Ca ion influx is important for IL-2 production but may not be needed for IL-2R expression.
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PMID:[On the mechanisms of human T cell proliferation induced by the 10B4 molecule]. 312 16

Erythropoietin (Epo) is the principal natural inducer of erythroid differentiation. The mechanisms by which signals generated at the Epo receptor (Epo-R) are transmitted to the nucleus are being explored. We now report that Epo strongly increases the activity of the transcription factor AP1 in both transformed and normal erythroid cells. Using antibodies to Fos and Jun, we have found that the Epo-induced AP1 heterodimer is composed primarily of authentic Fos and Jun proteins. Blocking protein kinase C (PKC) activity with H7 completely prevented the increase in AP1 activity in response to Epo. Importantly, the increase in AP1 activity was not due to increased expression of either c-fos or c-jun, as evidenced by the steady-state mRNA levels of both genes. Our results suggest that Epo may induce AP1 activity via a co- or posttranslational mechanism, presumably through modification of the Fos and/or Jun proteins.
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PMID:Erythropoietin activation of AP1 (Fos/Jun). 760 Dec 53


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