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)

The purpose of this work was to investigate the effects of electrical afterdischarge on protein kinase C (PKC) activity from bag cell neurons (BCNs) of Aplysia. Bilateral clusters of BCNs were divided: one cluster was stimulated to afterdischarge, the other was a control. Clusters were processed for PKC activity assay 5-120 min after electrical stimulation. Afterdischarge triggered a rapid and persistent increase in both calcium-activated and calcium-independent PKC activity.
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PMID:Persistent activation of calcium-activated and calcium-independent protein kinase C in response to electrical afterdischarge from peptidergic neurons of aplysia. 1040 18

Prolonged treatment with serotonin leads to long-term facilitation of sensory-to-motor neuron synapses in Aplysia. We have shown previously that there is a protein synthesis-dependent increase in an autonomous kinase activity that phosphorylates a protein kinase C substrate during an intermediate phase of this facilitation. Here, I report that the increase in autonomous activity was independent of RNA synthesis, suggesting it may play a role in the maintenance phase of synaptic facilitation. Immunoprecipitation experiments using an antibody specific to the Ca(2+)-independent protein kinase C, Apl II, demonstrated that the autonomous kinase activity increased by serotonin emanated from Apl II. Chelerythrine, an inhibitor targeted to the substrate binding site of protein kinase C, also blocked the autonomous kinase activity increased by serotonin. Using immunoblotting experiments and calphostin-C, an inhibitor targeted to the regulatory domain of protein kinase C, the autonomous activity is shown not to be a catalytic fragment of Apl II. Furthermore, a higher concentration of calphostin-C was required to inhibit autonomous kinase activity than regulated kinase activity, suggesting that calphostin-C's binding site in the regulatory domain of Apl II is modified in the autonomous kinase. These data suggest that an autonomous kinase derived from Apl II may play a role in synaptic facilitation in Aplysia.
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PMID:An autonomous kinase generated during long-term facilitation in Aplysia is related to the Ca(2+)-independent protein kinase C Apl II. 1045 6

We investigated activation of the two major neuronal protein kinase C (PKC) isoforms in Aplysia, Ca(2+)-activated Apl I and Ca(2+)-independent Apl II, during the induction and maintenance of behavioral sensitization of Aplysia defensive reflexes. Activation of PKC occurred during the training stimulus and persisted for at least 2 hr thereafter but was not maintained for 24 hr. The persistent activation required protein synthesis and was blocked by cyproheptidine, an agent that also blocked the initial activation of PKC. Persistent activation involved both an increase in membrane-associated Apl I and an increase in an autonomous kinase activity that may be related to a post-translational modification of Apl II. These results are consistent with the hypothesis that in addition to its role in producing the presynaptic facilitation of mechanosensory-motor neuron synapses that underlie short-term facilitation, PKC is needed for maintaining synaptic changes in an intermediate period that precedes the modifications accompanying consolidation of memory.
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PMID:Persistent activation of protein kinase C during the development of long-term facilitation in Aplysia. 1046 96

Nerve injury, tissue damage, and inflammation all cause hyperalgesia. A factor contributing to this increased sensitivity is a long-term (>24 hr) hyperexcitability (LTH) in the sensory neurons that mediate the responses. Using the cluster of nociceptive sensory neurons in Aplysia californica as a model, we are examining how inflammation induces LTH. A general inflammatory response was induced by inserting a gauze pad into the animal Within 4 days, the gauze is enmeshed in an amorphous material that contains hemocytes, which comprise a cellular immune system. Concurrently, LTH appears in both ipsilateral and contralateral sensory neurons. The LTH is manifest as increased action potential discharge to a normalized stimulus. Immunocytochemistry revealed that hemocytes have antigens recognized by antibodies to TGFbeta1, IL-6, and 5HT. When a localized inflammation was elicited on a nerve, hemocytes containing the TGFbeta1 antigen were present near axons within the nerve and those containing the IL-6 were on the surface. Western blots of hemocytes, or of gauze that had induced a foreign body response, contained a 28-kD polypeptide recognized by the anti-TGFbeta1 antibody. Exposure of the nervous system to recombinant human TGFbeta1 elicited increased firing of the nociceptive neurons and a decrease in threshold. The TGFbeta1 also caused an activation of protein kinase C (PKC) in axons but did not affect a kinase that is activated in axons after injury. Our findings, in conjunction with previous results, indicate that a TGFbeta1-homolog can modulate the activity of neurons that respond to noxious stimuli. This system could also contribute to interactions between the immune and nervous systems via regulation of PKC.
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PMID:Inflammation causes a long-term hyperexcitability in the nociceptive sensory neurons of Aplysia. 1049 14

Phosphorylation of calcium-activated protein kinase Cs (PKCs) at threonine 634 and/or threonine 641 increases during long term potentiation or associative learning in rodents. In the marine mollusk Aplysia, persistent activation of the calcium-activated PKC Apl I occurs during long term facilitation. We have raised an antibody to a peptide from PKC Apl I phosphorylated at threonines 613 and 620 (sites homologous to threonines 634 and 641). This antibody recognizes PKC Apl I only when it is phosphorylated at threonine 613. Both phorbol esters and serotonin increase the percentage of kinase phosphorylated at threonine 613 in Aplysia neurons. Furthermore, the pool of PKC that is phosphorylated at threonine 613 in neurons is resistant to both membrane translocation and down-regulation. Replacement of threonine 613 with alanine increased the affinity of PKC Apl I for calcium, suggesting that phosphorylation of this site may reduce the ability of PKC Apl I to translocate to membranes in the presence of calcium. We propose that phosphorylation of this site is important for removal of PKC from the membrane and may be a mechanism for negative feedback of PKC activation.
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PMID:Protein kinase C phosphorylated at a conserved threonine is retained in the cytoplasm. 1050 40

Long-term facilitation (LTF) of the sensory-to-motor synapses that mediate defensive reflexes in Aplysia requires induction of the transcription factor Aplysia CCAAT/enhancer binding protein (ApC/EBP) as an early response gene. We examined the time course of ApC/ EBP DNA binding during the induction of LTF: Binding activity was detected within 1 h of the sensitization treatment with serotonin, reached a maximum at 2 h, and decreased after 6 h. How are DNA binding and the turnover of ApC/EBP regulated? We find that phosphorylation of ApC/EBP by mitogen-activated protein (MAP) kinase is essential for binding. MAP kinase appears to be activated through protein kinase C. We also showed that ApC/EBP is degraded through the ubiquitin-proteasome pathway but that phosphorylation by MAP kinase renders it resistant to proteolysis. Thus, phosphorylation by MAP kinase is required for ApC/EBP to act as a transcription activator as well as to assure its stability early in the consolidation phase, when genes essential for the development of LTF begin to be expressed.
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PMID:Activation and degradation of the transcription factor C/EBP during long-term facilitation in Aplysia. 1058 1

Serotonergic modulation of the sensory neurons that mediate the gill- and tail-withdrawal reflexes of Aplysia is a useful model system for studies of neuronal plasticity that contributes to learning and memory. The effects of serotonin (5-HT) are mediated, in part, via two protein kinases (protein kinase A, PKA, and protein kinase C, PKC), which in turn, modulate at least four membrane currents, including a S ("serotonin-sensitive") K(+) current (I(K, S)), a steeply voltage-dependent K(+) current (I(K-V)), a slow component of the Ca(2+)-activated K(+) current (I(K,Ca-S)), and a L-type Ca(2+) current (I(Ca-L)). The present study investigated how the modulation of these currents altered the spike duration and excitability of sensory neurons and examined the relative contributions of PKA- and PKC-mediated effects to the actions of 5-HT. A Hodgkin-Huxley type model was developed that described the ionic conductances in the somata of sensory neurons. The descriptions of these currents and their modulation were based largely on voltage-clamp data from sensory neurons. Simulations were preformed with the program SNNAP (Simulator for Neural Networks and Action Potentials). The model was sufficient to replicate empirical data that describes the membrane currents, action potential waveform and excitability as well as their modulation by application of 5-HT, increased levels of adenosine cyclic monophosphate or application of active phorbol esters. In the model, modulation of I(K-V) by PKC played a dominate role in 5-HT-induced spike broadening, whereas the concurrent modulation of I(K,S) and I(K,Ca-S) by PKA primarily accounted for 5-HT-induced increases in excitability. Finally, simulations indicated that a PKC-induced increase in excitability resulted from decreases of I(K,S) and I(K,Ca-S), which was likely the indirect result of cross-talk between the PKC and PKA systems. The results provide several predictions that warrant additional experimental investigation and illustrate the importance of considering indirect as well as direct effects of modulatory agents on the modulation of membrane currents.
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PMID:Computational model of the serotonergic modulation of sensory neurons in Aplysia. 1060 29

Short-term behavioral sensitization of the gill-withdrawal reflex after tail stimuli in Aplysia leads to an enhancement of the connections between sensory and motor neurons of this reflex. Both behavioral sensitization and enhancement of the connection between sensory and motor neurons are importantly mediated by serotonin. Serotonin activates two types of receptors in the sensory neurons, one of which is coupled to the cAMP/protein kinase A (PKA) pathway and the other to the inositol triphosphate/protein kinase C (PKC) pathway. Here we describe a genetic approach to assessing the isolated contribution of the PKA pathway to short-term facilitation. We have cloned from Aplysia an octopamine receptor gene, Ap oa(1), that couples selectively to the cAMP/PKA pathway. We have ectopically expressed this receptor in Aplysia sensory neurons of the pleural ganglia, where it is not normally expressed. Activation of this receptor by octopamine stimulates all four presynaptic events involved in short-term synaptic facilitation that are normally produced by serotonin: (i) membrane depolarization; (ii) increased membrane excitability; (iii) increased spike duration; and (iv) presynaptic facilitation. These results indicate that the cAMP/PKA pathway alone is sufficient to produce all the features of presynaptic facilitation.
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PMID:Activation of a heterologously expressed octopamine receptor coupled only to adenylyl cyclase produces all the features of presynaptic facilitation in aplysia sensory neurons. 1067 41

Neuromuscular synapses in buccal muscle I3a of Aplysia are modulated by the small cardioactive peptide (SCP), a peptide cotransmitter that is intrinsic to the motor neurons, and by serotonin (5-HT) released from modulatory neurons that are extrinsic to the motor circuit. Although the modulation of excitatory junction potentials (EJPs) and contractions by 5-HT and SCP has been studied extensively in this muscle, little is known about the mechanisms that underlie the modulation. 5-HT and SCP, at 1 microM, were found to potently increase the level of cAMP in I3a. Therefore we investigated whether the activation of the cAMP pathway was sufficient to modulate EJPs and contractions. The direct activation of adenylyl cyclase with forskolin increased the level of cAMP, facilitated EJPs, and potentiated contractions. Indeed, the short-term effects of forskolin were very similar to all aspects of the short-term effects of 5-HT and SCP. Membrane-permeable cAMP analogues also mimicked the effects of 5-HT and SCP on EJPs and contractions. However, it seems likely that some effects of 5-HT are also mediated through other second-messenger pathways because low concentrations of 5-HT modulate EJPs and contractions but do not significantly increase cAMP levels in I3a. It is possible that lower concentrations of 5-HT function through receptors linked to protein kinase C (PKC) because phorbol, an activator of PKC, modulated EJPs and contractions without increasing the levels of cAMP. In conclusion, we provide evidence that pharmacological agents that activate the cAMP pathway mimicked most of the effects of 5-HT or SCP and that more than one second-messenger system appears to be involved in the modulation of the I3a neuromuscular system.
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PMID:Role of cAMP in the short-term modulation of a neuromuscular system in aplysia. 1071 80

Three distinct temporal phases of synaptic facilitation (short-, intermediate-, and long-term) are induced by serotonin (5-HT) at sensory (SN) to motor (MN) synapses in Aplysia. Here, we characterize two mechanistically distinct forms of intermediate-term facilitation (ITF) at tail SN-MN synapses. One form, activity-independent ITF, is produced by five spaced pulses of 5-HT in the absence of SN activity. Its induction requires protein synthesis, and its expression requires persistent activation of PKA but not PKC. The other form, activity-dependent ITF, is produced by a single pulse of 5-HT coincident with SN activation. Its induction does not require protein synthesis, and its expression requires persistent activation of PKC but not PKA. These results demonstrate that SN-MN synapses can exhibit two distinct forms of ITF that are mediated by parallel molecular pathways.
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PMID:Parallel molecular pathways mediate expression of distinct forms of intermediate-term facilitation at tail sensory-motor synapses in Aplysia. 1079 6


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