Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Methylxanthines have been shown to have a variety of effects on hematopoietic cell activation and function. These compounds inhibit cAMP-specific phosphodiesterase activity resulting in increased levels of intracellular cAMP. In the present study, we examined the effects of two methylxanthines, pentoxifylline (PTX) and caffeine, on the responses of both mouse and human lymphocytes to stimulation with polyclonal T- and B-cell mitogens, antigens, and the microbial superantigen, staphylococcal enterotoxin B (SEB). Both PTX and caffeine significantly inhibited mitogen- and SEB-induced proliferation by murine spleen cells, SEB- and antigen-induced proliferation and lymphokine secretion by murine Th1 and Th2 clones, and the generation of antigen-specific antibody producing murine spleen cells. These compounds also inhibited the proliferative responses of human lymphocytes to phytohemagglutinin, SEB, and tetanus toxoid. Efforts to determine whether these methylxanthine compounds mediated their inhibitory effects through a specific protein kinase pathway revealed a role for cAMP-dependent protein kinase A in methylxanthine-induced immunomodulation. However, it is possible that a protein kinase A-independent pathway may also be involved. These data demonstrate that the methylxanthines, PTX and caffeine, have profound effects on cells of the immune system and may have a potential use as immunotherapeutic agents in the treatment of various inflammatory conditions and autoimmune diseases.
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PMID:Methylxanthine-induced inhibition of the antigen- and superantigen-specific activation of T and B lymphocytes. 147 54

In previous studies, we have demonstrated that tetanus toxin (TT) inhibits macrophage (MO) lysozyme secretion and that the inhibition of secretion was not directly linked to perturbation of cytosolic calcium homeostasis. Because MO secretion in response to phorbol myristate acetate, a stimulus that activates protein kinase C (PKC), was inhibited by TT, we examined whether TT might interfere with PKC activity. We report that MOs treated with TT have diminished PKC activity. Purified TT as well as commercial TT diminished PKC activity, whereas heated TT and supernatant from which TT had been removed had no effect on PKC activity. We further examined PKC activity in homogenates of brain and spinal cord from mice manifesting generalized tetanus. Spinal cord cytosolic PKC activity (pmol/mg of protein per min) was depressed in TT-intoxicated mice (87.3 +/- 25) compared with controls (182.6 +/- 47; P less than .02, n = 7). In contrast, cytosolic protein kinase A activity was similar in control- and TT-treated MOs and mice. These results provide the first evidence that PKC activity is diminished during TT intoxication.
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PMID:Diminished activity of protein kinase C in tetanus toxin-treated macrophages and in the spinal cord of mice manifesting generalized tetanus intoxication. 328 62

1. Long-term potentiation (LTP) of synaptic transmission in autonomic ganglia is reviewed, together with the possible role of nitric oxide (NO) in this process. 2. Calcium levels in preganglionic nerve terminals are elevated during at least the induction phase of LTP following a tetanus as well as during LTP induced by transmitter substances acting on the nerve terminals. Of the large number of calcium-dependent processes in the nerve terminal that might affect transmitter release, only calcium-calmodulin has been shown to be important in both the induction and maintenance of LTP. 3. The possibility that there is a decrease in the open time of nerve-terminal potassium channels following a tetanus, leading to an increase in duration of the terminal action potential and hence an increase in calcium influx and transmitter release is considered. There is little evidence for such an effect as yet for preganglionic nerve terminals. 4. Phosphorylation of potassium channels by cAMP-dependent protein kinase can lead to their inactivation with consequent action potential broadening in some systems. Exogenous cAMP enhances synaptic efficacy at preganglionic nerve terminals. Whether this occurs through an inactivation of potassium channels is not known. 5. Nitric oxide (NO) synthase is present in both sympathetic ganglia and the ciliary ganglia. NO increases synaptic efficacy in both ganglia. In at least the case of ciliary ganglion this is due to elevation of quantal secretion. 6. NO can in some conditions increase the terminal action potential duration in ciliary ganglia, probably through decrease in the Ic potassium current. There is evidence that this happens through cGMP modulating cAMP phosphodiesterases, thereby affecting cAMP phosphorylation of the Ic channel. 7. Blocking NO synthase markedly decreases LTP following a tetanus in the ciliary ganglion. The possibility is considered that NO is released from the terminal during a tetanus and through altering cAMP phosphorylation of Ic enhances transmitter release.
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PMID:Nitric oxide release and long term potentiation at synapses in autonomic ganglia. 772 Oct 27

Repetitive activation of hippocampal mossy fibers evokes a long-term potentiation (LTP) of synaptic responses in pyramidal cells in the CA3 region that is independent of N-methyl-D-aspartate receptor activation. Previous results suggest that the site for both the induction and expression of this form of LTP is presynaptic. Experimental elevation of cyclic adenosine 3',5'-monophosphate (cAMP) both mimics and interferes with tetanus-induced mossy fiber LTP, and blockers of the cAMP cascade block mossy fiber LTP. It is proposed that calcium entry into the presynaptic terminal may activate Ca(2+)-calmodulin-sensitive adenylyl cyclase I which, through protein kinase A, causes a persistent enhancement of evoked glutamate release.
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PMID:Mediation of hippocampal mossy fiber long-term potentiation by cyclic AMP. 791 82

The present study shows that the protein kinase inhibitor staurosporine impairs the transient (< 60 min) potentiation (short-term potentiation) evoked by a weak tetanus to about the same extent as the more stable potentiation (long-term potentiation) evoked by a strong tetanus. This effect on short-term and long-term potentiation was seen both as a reduced magnitude and an increased decay rate, the latter being increased by about 50% compared to that seen under normal conditions. Comparison with potentiations evoked at different strengths in control solution suggested that much, but not all, of the increased decay rate observed in the presence of staurosporine could be explained by an impared induction. Staurosporine did not affect the N-methyl-D-aspartate-mediated field excitatory postsynaptic potential evoked by low-frequency stimulation or the magnitude of N-methyl-D-aspartate-mediated currents during high-frequency tetanization. This result suggests that the induction is impaired at a stage not related to the N-methyl-D-aspartate-mediated calcium influx. The present results suggest that short-term and long-term potentiation cannot be separated on the basis of protein kinase dependence. They do not support the common notion that short-term and long-term potentiation are mechanistically separate entities. Instead, the results support the view that long-term potentiation has a variable duration/stability dependent on the induction conditions and that protein kinase activation, via an action on induction mechanisms, contributes to its stabilization.
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PMID:Staurosporine impairs both short-term and long-term potentiation in the dentate gyrus in vitro. 815 38

1. The effects on catecholamine secretion of activation of protein kinase C and clostridial neurotoxins were examined in digitonin-permeabilized bovine adrenal chromaffin cells. 2. The enhancement by phorbol esters increased only the initial rate of secretion; later rates were unaffected. This enhancement was present over a wide range of Ca2+ concentrations and was elicited at 18 as well as at 27 degrees C. 3. Tetanus toxin inhibited both ATP-dependent and ATP-independent secretion, indicating that the tetanus toxin target is important during the final steps in the pathway. 4. Prior activation of protein kinase C by the phorbol ester 12-O-tetradecanoyl phorbol acetate rendered the primed state more sensitive to inhibition by tetanus toxin. The data indicate that a phosphorylated protein kinase C substrate is either identical to or closely associated with the tetanus toxin target protein at the final steps in the pathway. 5. The interaction between the effect of protein kinase activation and that of tetanus toxin suggests that protein kinase C activation does not stimulate a separate pathway of secretion but, rather, modulates the activity of the ongoing pathway. 6. The enhancement of secretion by protein kinase C is caused, at least in part, by a qualitative change in the characteristics of the primed state. This is indicated by the increased sensitivity of primed secretion to inhibition by tetanus toxin and a threefold increase in sensitivity of primed secretion to Ca2+. 7. Because activation of protein kinase C does not increase the later rates of secretion that are limited by ATP-dependent priming reactions, it is unlikely that enhancement of the maximal rate of secretion by TPA is due to an increased amount of the primed state. Instead, protein kinase C activation may increase the efficacy with which Ca2+ stimulates secretion at all Ca2+ concentrations.
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PMID:Protein kinase C and clostridial neurotoxins affect discrete and related steps in the secretory pathway. 819 81

Calcium-phospholipid-dependent protein kinase (PKC) has long been suggested to play an important role in modulating synaptic efficacy. We have created a strain of mice that lacks the gamma subtype of PKC to evaluate the significance of this brain-specific PKC isozyme in synaptic plasticity. Mutant mice are viable, develop normally, and have synaptic transmission that is indistinguishable from wild-type mice. Long-term potentiation (LTP), however, is greatly diminished in mutant animals, while two other forms of synaptic plasticity, long-term depression and paired-pulse facilitation, are normal. Surprisingly, when tetanus to evoke LTP was preceded by a low frequency stimulation, mutant animals displayed apparently normal LTP. We propose that PKC gamma is not part of the molecular machinery that produces LTP but is a key regulatory component.
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PMID:Modified hippocampal long-term potentiation in PKC gamma-mutant mice. 826 9

We have explored the mechanisms of mossy fiber long-term potentiation (LTP) at autapses in single-cell cultures of guinea pig hippocampal dentate granule cells. L-AP4-sensitive, but not insensitive, cells responded to a brief tetanus with a sustained potentiation in the synaptic responses. The induction of this LTP appeared identical to that observed in hippocampal mossy fiber synapses in situ, in that it required a rise in presynaptic Ca2+ and activation of protein kinase A. Its expression also appeared to be presynaptic and was due, at least in part, to events that occurred after the entry of Ca2+ and to the switching on of previously silent release sites.
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PMID:Long-term potentiation in cultures of single hippocampal granule cells: a presynaptic form of plasticity. 866 91

Long-term potentiation (LTP) and long-term depression (LTD) are calcium-dependent forms of synaptic plasticity observed in area CA1 of the hippocampus. Low-frequency tetani (1-5 Hz) activates protein phosphatases to induce LTD, whereas high-frequency tetani (> 25 Hz) activates protein kinases to induce LTP. A tetanus at an intermediate frequency (10 Hz), however, does not result in a change in synaptic efficacy [Dudek and Bear, (1992), Proc. Natl. Acad. Sci. USA, 89:4363-4367]. We hypothesized that the 10-Hz tetanus results in no long-term change in synaptic efficacy due to a balance of the activity of protein phosphatases and protein kinases. We manipulated protein kinase/phosphatase activity at a 10-Hz tetanus to test this hypothesis. A 10-Hz tetanus under normal conditions results in a transient depression which returns to baseline in 25 min. However, inhibiting kinase activity with the protein kinase inhibitor H-7, or decreasing extracellular calcium concentration, results in the 10-Hz tetanus, inducing LTD. Conversely, inhibiting phosphatase activity with the protein phosphatase inhibitor tautomycin, or increasing extracellular calcium concentration, results in the 10-Hz tetanus, inducing LTP. These results suggest that the relative balance of protein kinase and phosphatase activity (and/or the calcium levels activating them) determines the expression of specific forms of synaptic plasticity, and that these forms lie on a continuum.
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PMID:Protein kinase and phosphatase activity regulate the form of synaptic plasticity expressed. 889 Apr 51

Activation of protein kinase A (PKA) is known to facilitate synaptic transmission. Using synapses established by hippocampal neurons in culture, we show that dialysis of PKA inhibitors in the presynaptic neuron blocks synaptic facilitation produced by the adenylyl cyclase activator forskolin, demonstrating a presynaptic locus of action. Using ruthenium red, a tool that is known to stimulate exocytosis independently of Ca2+ influx, but in a manner sensitive to tetanus toxin, we find that the secretory process is directly up-regulated under conditions where the number of functional terminals remains unchanged, as revealed by imaging of FM1-43, a vital indicator of synaptic vesicle endocytosis. Taken together with our ultrastructural analysis that suggests no enhancement of docking, our data indicate that PKA causes synaptic facilitation by directly elevating the probability of exocytosis of individual vesicles in response to an invariant Ca2+ signal.
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PMID:Direct modulation of the secretory machinery underlies PKA-dependent synaptic facilitation in hippocampal neurons. 889 35


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