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)

Effects of intracellularly injected activators of protein kinase C on the InsP3-induced K+ current and the Ca2+-activated K+ current recorded from identified neurons (R9-R12) of Aplysia kurodai were investigated with conventional voltage-clamp and pressure-injection techniques. Intracellular injection of InsP3 into identified neurons produced a 4-aminopiridine (4-AP)-resistant, tetraethylammonium (TEA)-sensitive, and quinidine-sensitive K+ current similar to the Ca2+ activated K+ current elicited by direct injection of Ca2+ ions into the same neurons. The diacylglycerol analogue 1,2-oleoylacetylglycerol (OAG) at an intracellular concentration of 65 nM produced irreversible decreases in both the InsP3-induced K+ current and the Ca2+-activated K+ current. The phorbol 12,13-dibutyrate (PDBu) at an intracellular concentration of 150 nM also decreased irreversibly both the InsP3-induced K+ current and the Ca2+-activated K+ current. These results suggest that protein kinase C activators reduce both the InsP3-induced K+ current and the Ca2+-activated K+ current recorded from certain identified neurons of Aplysia and that protein kinase C reduces the ability of Ca2+ to open K+ channels rather than affecting the ability of InsP3 to release Ca2+ from intracellular stores.
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PMID:Protein kinase C activators reduce the inositol trisphosphate-induced outward current and the Ca2+-activated outward current in identified neurons of Aplysia. 254 Mar 37

One of the molecular mechanisms capable of regulating the physiological properties of neurones is the phosphorylation of ion channels and other cellular components by cyclic AMP-dependent protein kinase. Another protein kinase present in high concentrations in the mammalian brain is protein kinase C (a calcium/phosphatidylserine/diacylglycerol-dependent protein kinase), but there is no direct evidence, as yet, for the involvement of this enzyme in the control of neuronal excitability. We now present evidence that activation of endogenous protein kinase C by the tumour-promoting phorbol ester TPA (12-O-tetradecanoyl- phorbol-13-acetate), or intracellular injection of the purified enzyme, enhances the voltage-sensitive calcium current in bag cell neurones of the mollusc Aplysia.
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PMID:Enhancement of calcium current in Aplysia neurones by phorbol ester and protein kinase C. 257 17

1. We have investigated how activation of the inositol lipid second messenger pathway may contribute to modulation of membrane currents in tail motor neurons of Aplysia. Specifically, we examined the effects of injected inositol 1,4,5-trisphosphate (IP3) and analogues of diacylglycerol (DAG), both of which are products of the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2). 2. Injection of IP3 produced an outward current associated with an apparent increase in membrane conductance. Ion substitution experiments, the sensitivity of the response to low concentrations of TEA and its attenuation by intracellular injections of EGTA suggest that the current produced by injection of IP3 is a calcium-activated K+ current (IK,Ca). 3. The response to IP3 was mimicked by intracellular injection of Ca2+. Injection of Ca2+ produced an outward current that was associated with an apparent increase in input conductance of the membrane. The same manipulations that affected the response to IP3 (see above) also affected the response to injections of Ca2+. 4. Injections of activators of protein kinase C (PKC) produced a relatively slow inward current. The inward current has not been fully analyzed, but it does not appear to be due to the actions of any single conventional ion channel. 5. Activators of PKC attenuated responses to subsequent injections of IP3 indicating that one component of PIP2 hydrolysis can attenuate the other. 6. The results suggest that hydrolysis of inositol phospholipids is a mechanism for regulation of membrane properties in tail motor neurons of Aplysia.
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PMID:Inositol trisphosphate and activators of protein kinase C modulate membrane currents in tail motor neurons of Aplysia. 278 63

Following brief stimulation of an afferent pathway, the bag cell neurons of Aplysia undergo a dramatic change in excitability, resulting in a prolonged discharge of spontaneous action potentials. During the discharge, the action potentials of the bag cell neurons become enhanced in height and width. The afterdischarge triggers release of neuroactive peptides that initiate egg-laying behavior in this animal. Evidence suggests that changes in excitability of the bag cell neurons may be mediated by activation of protein kinase C (PKC) and cAMP-dependent protein kinase (cAMP-PK). PKC activators, such as the phorbol ester TPA (12-O-tetradecanoyl-13-phorbol acetate), enhance the amplitude of action potentials in isolated bag cell neurons in cell culture. These agents act by unmasking a previously covert species of voltage-dependent calcium channel resulting in an increase in calcium current. In the accompanying paper (Conn et al., 1989), we showed that H-7, a protein kinase inhibitor, inhibits the effect of TPA, and is a selective inhibitor of PKC relative to cAMP-PK in these cells. We now report that another PKC inhibitor, sphinganine, also inhibits the effect of TPA on action potential height and calcium current in cultured bag cell neurons, and that N-acetylsphinganine, an inactive sphinganine analog, fails to inhibit the effects of PKC activators. Although both H-7 and sphinganine prevent the effects of TPA when added prior to TPA addition, neither compound reverses the effects of TPA when added after the action potentials have already become enhanced by TPA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibitors of protein kinase C prevent enhancement of calcium current and action potentials in peptidergic neurons of Aplysia. 291 72

Previous studies on the biosynthesis of the peptide egg-laying hormone (ELH) of Aplysia have suggested that the increase in cAMP levels associated with the initiation of a bag cell discharge stimulated ELH synthesis, whereas the calcium influx associated with the discharge inhibits it. This report provides additional documentation of the inhibitory role of calcium. Inhibition by the calcium ionophore A23187 was shown to be dependent on the presence of extracellular calcium. A23187 inhibited ELH synthesis and exposure to 0 Ca2+/2 mM EGTA medium stimulated it in bag cell somata surgically deprived of their sites of synaptic input. The tumor-promoting phorbol ester, TPA, inhibited ELH biosynthesis in a calcium-dependent fashion, whereas the non-tumor-promoting 4 alpha-phorbol did not. These results are consistent with the hypothesis that calcium entry during bag cell discharge may inhibit ELH synthesis via activation of protein kinase C, thus counteracting the stimulation by cAMP early in the discharge. Such a mechanism could precisely regulate the production of ELH molecules to replace those lost by secretion.
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PMID:Calcium and protein kinase C inhibit biosynthesis of Aplysia egg-laying hormone. 309 55

1.) Application of serotonin to Aplysia sensory neurons can result in facilitated synaptic transmission, both short- and long-term. This facilitation is likely to be produced by a complex set of molecular mechanisms: serotonin activates adenylate cyclase, increasing cAMP and protein kinase (Cedar and Schwartz, 1972); serotonin also changes the subcellular distribution of the Ca2+/calmodulin-dependent protein kinase (Saitoh and Schwartz, 1983). Recently, phorbol esters also have been shown to produce facilitation. We have therefore investigated how protein kinase C (PKC) participates in serotonin-mediated synaptic facilitation. 2.) We found that the Aplysia genome encodes PKC, which is expressed in nervous tissue as at least two abundant transcripts (about 0.003% of the total message). Its inferred amino acid sequence is 85% homologous to that of enzymes from mammals and Drosophila, and over 95% homologous if compared to both. The specific activity of the Aplysia kinase is comparable to that found in rat brain, with similar reaction parameters and dependencies on phosphatidylserine (PS), Ca2+, diacylglycerol and phorbol esters. While PKC is found on neuronal membrane in the basal state, the PKC activators, Ca2+ and phorbol esters, further translocate the kinase to membrane in crude extracts of neuronal tissue. The amounts of membrane-bound PKC, as determined by 3H-phorbol-ester binding, are greatest in neuropil and nerve. 3.) Exposure of sensory neurons and their terminals in Aplysia pleural-pedal ganglia to facilitating doses of either phorbol ester or serotonin results in the translocation of PKC from cytosol to membrane, activating the enzyme. cAMP does not produce this translocation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation of protein kinase C by serotonin: biochemical evidence that it participates in the mechanisms underlying facilitation in Aplysia. 327 94

It has been shown that intracellular injection of protein kinase C (calcium/phosphatidylserine/diacylglycerol-dependent protein kinase), purified from mammalian brain, or application of the tumor-promoting phorbol diester, 12-O-tetradecanoyl-13-phorbol acetate (TPA), leads to an enhancement of calcium currents in the bag cell neurons of Aplysia. We now present evidence of an endogenous enzyme in bag cell neurons which is activated by TPA and which has properties similar to those of mammalian protein kinase C. Calcium/phosphatidylserine/diacylglycerol-dependent protein kinase activity was found in both cytosolic and particulate fractions prepared from isolated clusters of bag cell neurons. This endogenous enzyme phosphorylated an 87,000-dalton protein from bovine brain, which appears to be a specific substrate for protein kinase C, as well as several substrates present in cytosolic fractions prepared from isolated bag cell clusters. Similar results were obtained using preparations made from pooled head ganglia from Aplysia. The pharmacological properties of the calcium/phosphatidylserine/diacylglycerol-dependent protein kinase activity in the Aplysia nervous system were similar to those of protein kinase C from mammalian tissues. Thus, the same group of endogenous substrate proteins were phosphorylated when diacylglycerol was replaced by TPA in cytosolic fractions prepared from isolated bag cell clusters. Non-tumor-promoting phorbols (4-alpha-phorbol, 4-alpha-phorbol-12,13-didecanoate, and 4-O-methyl-12-O-tetradecanoylphorbol-13-acetate) did not stimulate protein phosphorylation in these preparations. Phosphorylation by the Aplysia calcium/phosphatidylserine/diacylglycerol-dependent protein kinase was inhibited by polymixin B sulfate, by calmodulin, and by the "calmodulin antagonists" trifluoperazine, calmidazolium and W7.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Calcium/phosphatidylserine/diacylglycerol-dependent protein phosphorylation in the Aplysia nervous system. 404 49

Increases in activity of both protein kinase A (PKA) and protein kinase C (PKC) contribute to short-term facilitation of Aplysia sensorimotor synapses evoked by serotonin (5-HT). We report here that increasing levels of cAMP in sensory neurons evokes increases in both synaptic efficacy and in the number of sensory neuron varicosities contacting the major axons of motor cell L7 at intermediate times (3 hr) that persist for 24 hr. Treatment with phorbol esters results in a large transient increase in synaptic efficacy that is accompanied by a large transient increase in the number of sensory neuron varicosities with the newest varicosities most susceptible to elimination. The reversal of the synaptic facilitation and the structural changes does not appear to be the result of long-term inhibitory actions of persistent PKC activation by phorbol esters, since changes in synaptic efficacy can be evoked by additional applications of either phorbol esters or 5-HT. The short-lived changes in structure evoked by phorbol esters occur in preexisting sensory neurites and not by new growth, since increases in PKC activity with phorbol esters lead to reductions in neurite extension and to retractions by sensory neuron growth cones. The action of phorbol esters on growth cone extension is reversible with washout. The results suggest that increases in PKA and PKC activities by 5-HT contribute to short (minutes) and intermediate (hours) forms of facilitation of sensorimotor synapses while increases in PKA activity also mediate long-term (days) maintenance of synaptic facilitation.
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PMID:Transient versus persistent functional and structural changes associated with facilitation of Aplysia sensorimotor synapses are second messenger dependent. 747 3

Alterations in the parameters of action potentials upon changes in protein kinase C (PKC) activity were studied on neurons of the visceral ganglion of Aplysia californica. The amplitude and maximum speed of the up-and downstroke of the action potentials (APs) were measured. Intracellularly injected PKC and intra- and extracellularly applied phorbol-12,13-diacetate (PDAc) had similar effects on the Aplysia neurons, the most prominent being an increase of the upstroke speed of the AP in every neuron. The non-PKC-activating 4 alpha-phorbol didecanoate had no effect, and the effects of the PKC blocker H-7 were opposite to those of PDAc. It was concluded that the changes of the AP evoked by PDAc are mediated through PKC activation.
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PMID:Alterations in the action potential of Aplysia neurons evoked by a phorbolester are mediated by protein kinase C. 758 98

1. Electrical stimulation of an afferent nerve triggers a 30-min period of firing of action potentials in the bag cell neurons of Aplysia californica. This afterdischarge causes the animal to undergo a long-lasting sequence of stereotyped reproductive behaviors culminating in laying of eggs. The connective sheath surrounding the clusters of bag cell neurons is interspersed with a network of particles that are immunoreactive to an antiserum raised against the tetrapeptide neurotransmitter Phe-Met-Arg-Phe-amide (FMRFa). Because the sheath is known to be rich in processes from the bag cell neurons, these data suggest that an FMRFa-like peptide may be located in neuronal processes that are in close contact with those of the bag cell neurons. 2. Application of FMRFa to bag cell neurons in intact abdominal ganglia effectively suppresses the onset of the afterdischarge in response to electrical stimulation and terminates an ongoing afterdischarge in a reversible manner. 3. Application of FMRFa to isolated bag cell neurons in primary cell culture causes an attenuation of the amplitude of evoked action potentials. This could be attributed in part to an attenuation of the voltage-activated calcium current, which in voltage-clamp experiments was found to be reduced by 10-40%. 4. Application of FMRFa to bag cell neuron in primary culture also causes a hyperpolarization of the membrane potential by activating an outward current with a reversal potential of approximately -67 mV. Ion substitution experiments, together with application of channel blockers, indicate that this current is carried by both potassium and chloride ions. Activation of this current is suppressed by treatment of the cells with either a cyclic AMP analogue or a phorbol ester activator of protein kinase C. 5. FMRFa exerts a powerful inhibitory influence on the bag cell neurons by altering the properties of ion currents involved in both the generation of action potentials and control of the resting potential. This suggests that this neuropeptide plays a role in the regulation of the onset of afterdischarge in vivo.
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PMID:The peptide FMRFa terminates a discharge in Aplysia bag cell neurons by modulating calcium, potassium, and chloride conductances. 768 3


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