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:2.7.11.13 (protein kinase C)
49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ca(2+)-independent or novel protein kinase Cs (nPKCs) contain an N-terminal C2 domain of unknown function. Removal of the C2 domain of the Aplysia nPKC Apl II allows activation of the enzyme at lower concentrations of phosphatidylserine, suggesting an inhibitory role for the C2 domain in enzyme activation. However, the mechanism for C2 domain-mediated inhibition is not known. Mapping of the autophosphorylation sites for protein kinase C (PKC) Apl II reveals four phosphopeptides in the regulatory domain of PKC Apl II, two of which are in the C2 domain at serine 2 and serine 36. Unlike most PKC autophosphorylation sites, these serines could be phosphorylated in trans. Interestingly, phosphorylation of serine 36 increased binding of the C2 domain to phosphatidylserine membranes in vitro. In cells, PKC Apl II phosphorylation at serine 36 was increased by PKC activators, and PKC phosphorylated at this position translocated more efficiently to membranes. Moreover, mutation of serine 36 to alanine significantly reduced membrane translocation of PKC Apl II. We suggest that translocation of nPKCs is regulated by phosphorylation of the C2 domain.
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PMID:Membrane translocation of novel protein kinase Cs is regulated by phosphorylation of the C2 domain. 1107 45

At nondepressed Aplysia sensory to motor synapses, serotonin (5-HT) facilitates transmitter release primarily through a protein kinase A pathway. In contrast, at depressed Aplysia sensory to motor synapses, 5-HT facilitates transmitter release primarily through a protein kinase C (PKC)-dependent pathway. It is known that only two phorbol ester-activated PKC isoforms, the Ca(2+)-dependent PKC Apl I and the Ca(2+)-independent PKC Apl II, exist in the Aplysia nervous system. For the first time, we have now been able to functionally determine which isoform of PKC is involved in a particular form of plasticity. We microinjected cultured sensorimotor pairs of neurons with various PKC constructs tagged with the enhanced green fluorescent protein as a reporter for successful plasmid expression. Our results demonstrate that short-term facilitation of depressed synapses is mediated by PKC Apl II. Dominant-negative PKC Apl II, but not dominant-negative PKC Apl I, disrupted the normal kinetics of 5-HT-induced facilitation by completely blocking its rapid onset. This effect was specific to depressed synapses, because dominant-negative PKC Apl II did not inhibit 5-HT-mediated facilitation of nondepressed synapses. Our results suggest that not only different signal transduction pathways but also different isoforms of a specific cascade may mediate physiological responses according to the state of a synapse.
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PMID:Ca2+-independent protein kinase C Apl II mediates the serotonin-induced facilitation at depressed aplysia sensorimotor synapses. 1116 Mar 95

The identification of tags that can specifically mark activated synapses is important for understanding how long-term synaptic changes can be restricted to specific synapses. The maintenance of synapse-specific facilitation in Aplysia sensory to motor neuron cultures can be blocked by inhibitors of translation and by the drug rapamycin, which specifically blocks a signaling pathway that regulates phosphorylation of translational regulators. One important target of rapamycin is the phosphorylation and subsequent activation of S6 kinase. To test whether S6 kinase is the target for the ability of rapamycin to block synapse-specific facilitation in Aplysia, we cloned Aplysia S6 kinase, its substrate S6, and the S6 kinase kinase phosphoinositide-dependent kinase 1 (PDK-1). Serotonin, which induces synapse-specific facilitation, increased phosphorylation of Aplysia S6 kinase at threonine 399 in a rapamycin-sensitive manner in Aplysia synaptosomes. The phosphorylation of threonine 399 by 5-HT was independent of phosphoinositide-3 kinase, dependent on PKA and PKC, and occluded by the phosphatase inhibitor calyculin-A. 5-HT also increased S6 kinase activity and led to increased phosphorylation of S6 in synaptosomes. 5-HT increased levels of S6 in synaptosomes because of a rapamycin-sensitive increase in translation-stabilization of S6. Aplysia PDK-1 bound to and phosphorylated Aplysia S6 kinase but only modulated phosphorylation of threonine 399 indirectly. These results suggest a mechanism by which the levels of translation factors can be increased specifically at activated synapses generating a long-lasting synaptic tag.
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PMID:Serotonin activates S6 kinase in a rapamycin-sensitive manner in Aplysia synaptosomes. 1116 Apr 19

Accumulating evidence suggests that many ion channels reside within a multiprotein complex that contains kinases and other signaling molecules. The role of the adaptor proteins that physically link these complexes together for the purposes of ion channel modulation, however, has been little explored. Here, we examine the protein-protein interactions required for regulation of an Aplysia bag cell neuron cation channel by a closely associated protein kinase C (PKC). In inside-out patches, the PKC-dependent enhancement of cation channel open probability could be prevented by the src homology 3 (SH3) domain, presumably by disrupting a link between the channel and the kinase. SH3 and PDZ domains from other proteins were ineffective. Modulation was also prevented by an SH3 motif peptide that preferentially binds the SH3 domain of src. Furthermore, whole-cell depolarizations elicited by cation channel activation were decreased by the src SH3 domain. These data suggest that the cation channel-PKC association may require SH3 domain-mediated interactions to bring about modulation, promote membrane depolarization, and initiate prolonged changes in bag cell neuron excitability. In general, protein-protein interactions between ion channels and protein kinases may be a prominent mechanism underlying neuromodulation.
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PMID:Protein kinase modulation of a neuronal cation channel requires protein-protein interactions mediated by an Src homology 3 domain. 1175 82

Synaptic plasticity can last from a fraction of a second to weeks depending on how it was induced. The mechanisms that underlie short-, intermediate-, and long-term plasticity have been intensively studied at central synapses of both vertebrates and invertebrates; however, peripheral plasticity has not received as much attention. In this study, we investigated the mechanisms that contribute to a persistent form of plasticity at neuromuscular synapses in buccal muscle I3a of Aplysia. These synapses are reversibly facilitated by the small cardioactive peptide (SCP), a peptide cotransmitter that is intrinsic to the motor neurons, and persistently facilitated by serotonin (5HT) released from modulatory neurons that are extrinsic to the motor circuit. Many of the short-term effects of 5HT and SCP are mediated by the cAMP pathway, but little is known about the mechanisms that underlie persistent modulation. We were able to eliminate several possible mechanisms. One of these was the possibility that the apparent reversal of SCP's effects was due to desensitization of the SCP receptor. Superfusion for longer periods or with higher concentrations of SCP indicate that the SCP receptors do not desensitize. We also determined that new protein synthesis is not required for the persistent facilitation of EJPs. Another possibility was that 5HT was taken up and slowly re-released. Our results suggest that this mechanism is also unlikely. Activation of the cAMP pathway does not appear to mediate persistent effects; however, 5HT as well as SCP does cause persistent increases in cAMP levels that can prime I3a synapses and increase the effectiveness of activators of the cAMP pathway. Instead, the persistent effects of 5HT are mimicked by phorbol, suggesting that protein kinase C or an Aplysia homologue of unc13 may mediate these effects. These results, in combination with results from experiments on the sensory neurons that contribute to withdrawal reflexes in Aplysia, suggest that the mechanisms for intermediate- and long-term facilitation may reside in all of the synapses involved in the sensory to motor response reflex.
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PMID:Mechanisms involved in persistent facilitation of neuromuscular synapses in aplysia. 1192 20

Phosphorylation of protein kinase Cs (PKCs) by phosphoinositide-dependent kinase I (PDK) is critical for PKC activity. In the nervous system of the marine mollusk Aplysia, there are only two major PKC isoforms, the calcium-activated PKC Apl I and the calcium-independent PKC Apl II, and both PKCs are persistently activated during intermediate memory. We monitored the PDK-dependent phosphorylation of PKC Apl I and PKC Apl II using phosphopeptide antibodies. During persistent activation of PKCs in Aplysia neurons, there is a significant increase in the amount of PDK-phosphorylated PKC Apl II in the particulate fraction but no increase in the amount of PKC Apl I phosphorylated by PDK. PDK phosphorylation of PKCs was not sensitive to inhibitors of phosphatidylinositol 3-kinase, PKC, or expression of a kinase-inactive PDK. Localization of PDK-phosphorylated PKC Apl II using immunocytochemistry revealed an enrichment of phosphorylated PKC Apl II at the plasma membrane. These data suggest that increased PDK phosphorylation of PKC Apl II is important for persistent kinase activation.
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PMID:Phosphoinositide-dependent kinase phosphorylation of protein kinase C Apl II increases during intermediate facilitation in aplysia. 1214 Feb 80

The Ca(2+)-independent protein kinase C (PKC) Apl II, but not the Ca(2+)-activated PKC Apl I, becomes autonomously active during intermediate periods of facilitation in Aplysia neurons. We examined the ability of superoxide formed by the enzymatic reaction of xanthine with xanthine oxidase (X/XO) to induce autonomous activity of PKCs in Aplysia. X/XO stimulated autonomous PKC activity in Aplysia nervous system homogenates, but this activity resulted solely from activation of PKC Apl I. PKC Apl I is also more sensitive to activation by X/XO when expressed in insect cells. Our results suggest that oxidation can autonomously activate PKC Apl I in the Aplysia nervous system, but that the activation of PKC Apl II during synaptic facilitation is not due to oxidation of the enzyme.
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PMID:Oxidation induces autonomous activation of protein kinase C Apl I, but not protein kinase C Apl II in homogenates of Aplysia neurons. 1218 25

Activation of protein kinase C (PKC) increases microtubule (MT) growth lifetimes, resulting in extension of a nocodazole-sensitive population of MTs in Aplysia growth cones. We examined whether the two phorbol ester-activated PKCs in Aplysia, the Ca(2+)-activated PKC Apl I and the Ca(2+)-independent PKC Apl II, are associated with these MTs. Phorbol esters translocated PKC to the Triton X-100-insoluble fraction, and a significant portion of this translocated pool was sensitive to low concentrations of nocodazole. Low doses of nocodazole had no effect on the amount of PKC in the Triton X-100-insoluble fraction in the absence of phorbol esters, whereas higher doses of nocodazole reduced basal levels of PKC Apl II. The F-actin cytoskeletal disrupter, latrunculin A, removed both PKCs from the Triton X-100-insoluble fraction in both control and phorbol ester-treated nervous systems. PKC Apl II also directly interacted with purified MTs. In detergent-extracted cells, both PKCs immunolocalized predominantly with MTs. PKCs were associated with newly formed MTs invading the actin-rich peripheral growth cone domain after PKC activation. Our results are consistent with a central role for PKCs in regulating MT extension.
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PMID:Protein kinase C isoforms are translocated to microtubules in neurons. 1218 53

Stimulation of the bag cell neurons of Aplysia activates several biochemical pathways, including protein kinase C (PKC), and alters their excitability for many hours. After an approximately 30 min afterdischarge, these neurons enter an approximately 18 hr inhibited state during which additional stimulation fails to evoke discharges. In vivo, this refractory period limits the frequency of reproductive behaviors associated with egg laying. We have now examined the role of Ca2+-activated K+ (BK) currents in the refractory period. Outward currents gated by both intracellular Ca2+ and depolarization, with pharmacological characteristics of BK currents, were recorded in isolated bag cell neurons. These currents were enhanced by the BK channel activators phloretin and 1,3-dihydro-1-[2-hydroxy-5-(trifluoro-methyl)phenyl]-5-trifluoromethyl-2H-benzimidazol-2-one and inhibited by the BK blocker paxilline. The BK component of K+ current was enhanced by 12-O-tetradecanoyl-phorbol-13-acetate, an activator of PKC, and this effect was blocked by sphinganine and PKC(19-36), inhibitors of PKC in bag cell neurons. To test whether the BK current is altered during the refractory period, intact clusters were stimulated to afterdischarge, and neurons were isolated after the clusters had entered the refractory period. Compared with unstimulated cells, current density was almost doubled in refractory neurons. This increase in current was inhibited by preincubating clusters in sphinganine. Treatment of refractory clusters with paxilline significantly restored the ability of stimulation to evoke afterdischarges. Conversely, application of phloretin to previously unstimulated clusters inhibited the onset of afterdischarges. These results indicate that a prolonged increase in BK channel activity contributes to the prolonged refractory period of the bag cell neurons.
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PMID:Prolonged activation of Ca2+-activated K+ current contributes to the long-lasting refractory period of Aplysia bag cell neurons. 1245 Nov 14

The protein kinase C (PKC) family of enzymes is broadly distributed and has been implicated in a diverse array of cellular functions. Recent evidence supporting PKC involvement in the regulation of the Limulus choline cotransporter prompted us to clone PKC from a Limulus central nervous system (CNS) cDNA library. An Aplysia californica calcium independent PKC (Apl II) cDNA probe was used to screen the library and 5' RACE SMART PCR was used to obtain the full-length sequence. The resulting cDNA, which included 5' and 3' nontranslation regions, was 4675 bp. Analysis of the encoded peptide sequence using the Swiss-prot database revealed at least 58% identity to PKC epsilon. A commercial polyclonal antibody against PKC epsilon was used in Western blots to positively label a 30 kDa protein from Limulus CNS and the expressed fusion protein of the encoded sequence. These data support the presence of a newly identified PKC-like homolog in Limulus which likely represents a PKC epsilon equivalent.
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PMID:Molecular cloning and identification of a putative PKC epsilon cDNA from Limulus polyphemus brain. 1249 76


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