EC:2.7.11.13 - FACTA Search

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 effects of serotonin (5-HT) and GABA on two Ca2+ currents, a transient low-voltage-activated current (tLVA) and a sustained high-voltage-activated current (sHVA) were examined in isolated photoreceptors of Hermissenda. The sHVA current was blocked by 5-HT and reduced by activation of protein kinase C (PKC) with phorbol 12-myristate 13-acetate. The effects of 5-HT were transiently reversed by staurosporine and partially blocked by the PKC inhibitor peptide [PKC(19-36)]. GABA enhanced both the tLVA and sHVA currents at low concentrations (5 nM to 5 microM) and reduced the sHVA current at high concentrations (>10 microM). The GABA-mediated enhancement of the Ca2+ current at low concentrations was sensitive to block by picrotoxin. The protein kinase A (PKA) inhibitor peptide [PKI(6-22)amide] blocked enhancement of both Ca2+ currents produced by cAMP analogs and GABA, suggesting that the effects at low concentrations may be PKA mediated. Caged GTP-gamma-S released by flash photolysis reduced the sHVA current, and pretreatment of the photoreceptors with pertussis toxin blocked the effects of higher concentrations of GABA, indicating that at higher concentrations, the effects may be G-protein mediated.
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PMID:Protein kinase and G-protein regulation of Ca2+ currents in Hermissenda photoreceptors by 5-HT and GABA. 876 66

Insulin-like growth factor-I elicits a long-term depression of the glutamate-induced GABA release in the adult rat cerebellum that lasts at least several hours. We studied whether protein kinase C and nitric oxide may be involved in this effect of insulin-like growth factor-I on GABA release since both signalling pathways have been implicated in other forms of neuromodulation in the cerebellum. By using microdialysis in the adult rat cerebellum, we found that either an inhibitor of protein kinase C (staurosporine) or of nitric oxide synthase (Nw-nitro-L-arginine methyl ester) counteracted the long-term, but not the acute effects of insulin-like growth factor-I on glutamate-induced GABA release. On the contrary, when either an activator of protein kinase C (phorbol ester), or an nitric oxide donor (L-arginine), were given with glutamate, they mimicked only the acute effects of insulin-like growth factor-I on glutamate-induced GABA release. Finally, when both protein kinase C and nitric oxide-synthase were simultaneously inhibited by conjoint administration of staurosporine and Nw-nitro-L-arginine methyl ester, a complete blockage of both the short and the long-term effects of insulin-like growth factor-I on GABA release was obtained. These results, indicate that: (i) activation by insulin-like growth factor-I of either the protein kinase C or nitric oxide-signalling pathways is sufficient for the short-term inhibition of glutamate-induced GABA release; and (ii) simultaneous activation of both the protein kinase C and the nitric oxide signalling pathways is necessary for insulin-like growth factor-I to induce a long-term depression of GABA responses to glutamate. Thus, long-term depression of glutamate-induced GABA release by insulin-like growth factor-I in the cerebellum is mediated by simultaneous activation of both protein kinase C and nitric oxide-signalling pathways.
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PMID:Involvement of protein kinase C and nitric oxide in the modulation by insulin-like growth factor-I of glutamate-induced GABA release in the cerebellum. 884 70

1. Protein kinase modulation of gamma-aminobutyric acid-A (GABAA)- and glycine-activated Cl- currents in freshly dissociated, morphologically identified rabbit retinal rod bipolar cells was studied under voltage clamp with the use of the whole cell patch-clamp technique. Responses to pulses of GABA and glycine were monitored before, during, and after application of adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase (PKA) and protein kinase C (PKC) activators, inactive analogues, and inhibitors. 2. Bath perfusion with either forskolin, an adenylate cyclase activator, or its inactive analogue, 1,9 dideoxyforskolin, reduced the GABA-activated Cl- currents by 30-50%; coapplication of N-[2-(Methylamino)ethyl]-5-isoquinolinesulfonamide hydrochloride (H-8), a PKA inhibitor, did not prevent the forskolin effects. The membrane-permeable cAMP analogues, 8-bromo-cAMP and 8-(4-Chlorophenylthio)-cAMP, and intracellularly dialyzed cAMP, did not modulate either the GABA- or glycine-activated Cl- current. Perfusion of the phosphodiesterase inhibitor 3-isobutyl-1-methylxantine (IBMX) had no direct effect on the GABA-activated current and did not alter the results with cAMP or its membrane-permeable analogues. Collectively, these results make it very unlikely that PKA represents an important mechanism of either GABAA or glycine channel modulation in the rabbit rod bipolar cell. 3. Although the isoquinoline sulfonamide protein kinase inhibitor H-8 was without discernible effect, the related compounds 1-(5-Isoquinolinesulfonyl)-2-methylpiperazine dihydrochlorine (H-7) and N-(2-Aminoethyl)-5-isoquinolinesulfonamide dihydrochloride (H-9) both dramatically reduced the GABA response. H-7 also strongly reduced the response to glycine, whereas H-8 had no effect and H-9 had an intermediate effect. Because only certain members of this inhibitor class of agents proved effective, and their effectiveness appeared unrelated to the established activity profiles, these agents probably inhibit the Cl- currents in a phosphorylation-independent manner. Direct interaction of these inhibitors with binding sites in the GABAA receptor-channel complex has been previously reported in some other preparations. 4. The phorbol ester and PKC activator phorbol 12,13 dibutyrate (PDB) led to a 35-55% reduction in the GABA-activated Cl- current of the rod bipolar cell. The broad-spectrum kinase inhibitor staurosporine, and the more PKC-specific inhibitor calphostin C, had no direct effect on GABA responses, but prevented Cl- current reduction when coapplied with PDB. Phorbol 12-myristate 13-acetate (PMA) reduced the GABA-activated current in a fashion very similar to PDB. Staurosporine and calphostin C blocked the PMA effect. No reduction of Cl- current was seen with the inactive analogue, 4-alpha-PMA, used as a control for PKC-independent phorbol ester effects. 5. PDB effectively reduced the GABA-activated Cl- current of the rod bipolar cell at low concentrations, whereas PMA had a diminished effect at low concentrations. This is consistent with the reported concentration-dependent abilities of these agents to promote translocation of PKC-alpha immunoreactivity from the membrane to the cytosolic compartment in the rabbit retinal rod bipolar cell. Collectively, the data from phorbol esters, inactive analogues, and kinase inhibitors support the existence of a PKC-mediated mechanism for GABA-activated Cl- current reduction in these cells. 6. The naphthalenesulfonamide PKC activator N-(n-Heptyl)-5-chloro-1-naphthalenesulfonamide (SC-10) also potently and reversibly reduced the GABA-activated current. Staurosporine and calphostin C eliminated this effect. When the nonhydrolyzable guanosine 5'-triphosphate (GTP) analogue guanosine 5'-O-(3-thiotriphosphate) tetralithium salt (GTP-gamma-S) replaced GTP in the recording pipette, the SC-10-mediated GABA current reduction became irreversible.(ABSTRACT TRUNCATED)
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PMID:Protein kinase modulation of GABAA currents in rabbit retinal rod bipolar cells. 893 Feb 56

The purpose of the present study was to elucidate the physiological mechanisms that determine the activation of protein kinase C (PKC) in rod bipolar cells (RBC) of mouse and goldfish. The localization of PKC in RBC was examined using immunoreactivity (IR) against the alpha species of the enzyme. After incubating the whole retina or dissociated cells in control or test solutions, PKC-IR was performed on retinal transverse sections or on isolated cells. Cell depolarization induced the transport of the PKC to the synaptic terminal of RBC. The transport of the enzyme was also induced upon incubating dissociated cells in a solution containing phorbol esters. Enzyme transport was inhibited when the isolated retina was incubated in solutions containing GABA or nifedipine. We conclude that calcium and diacylglycerol, which contribute to the activation of PKC in RBC, induce transport of the enzyme to the synaptic terminal where it is presumed to play its functional role.
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PMID:Protein kinase C localization in the synaptic terminal of rod bipolar cells. 893 Sep 84

Anoxia/ischemia in the CNS is a common and devastating phenomenon. It is possible that the best hopes for protection against anoxic/ischemic injury may involve recruiting and/or augmenting any autoprotective systems that evolution has provided for the CNS. We describe here the existence of such an autoprotective system present in CNS white matter. White matter is both well suited to studying extrasynaptic systems, such as the system we describe here, and is a highly appropriate target for research into anoxic-ischemic injury in its own right. We show that white matter contains functional GABAB and adenosine receptors that respond to an anoxic efflux of GABA and adenosine by recruiting a convergent intracellular mechanism involving protein kinase C (PKC). The net result of this receptor-mediated cascade is an increase in resistance to anoxia, which presumably allows CNS white matter to tolerate better a common class of ischemic events that are located solely in white matter and that comprises approximately 25% of all strokes seen clinically.
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PMID:Autoprotective mechanisms in the CNS: some new lessons from white matter. 896 97

Tight-seal whole-cell recordings from CA1 pyramidal cells of rodent hippocampus were performed to study GABAB receptor-mediated inhibition of tetrodotoxin (TTX)-resistant IP-SCs. IPSCs were recorded in the presence of TTX and glutamate receptor antagonists. (R)-(-)-baclofen reduced the frequency of TTX-resistant IPSCs by a presynaptic action. The inhibition by (R)-(-)-baclofen was concentration-dependent, was not mimicked by the less effective enantiomer (S)-(+)-baclofen, and was blocked by the GABAB receptor antagonist CGP 55845A, suggesting a specific effect on GABAB receptors. The inhibition persisted in the presence of the Ca2+ channel blocker Cd2+. There was no requirement for an activation of K+ conductances by (R)-(-)-baclofen, because the inhibition of TTX-resistant IPSCs persisted in Ba2+ and Cd2+. Because the time courses of TTX-resistant IPSCs were not changed by (R)-(-)-baclofen, there was no evidence for a selective inhibition of quantal release from a subgroup of GABAergic terminals. (R)-(-)-baclofen reduced the frequency of TTX-resistant IPSCs in guinea pigs and Wistar rats, whereas the inhibition was much smaller in Sprague Dawley rats. In Cd2+ and Ba2+, beta-phorbol-12,13-dibutyrate and forskolin enhanced the frequency of TTX-resistant IPSCs. Only beta-phorbol-12, 13-dibutyrate reduced the inhibition by (R)-(-)-baclofen. We conclude that GABAB receptors inhibit TTX-resistant GABA release through a mechanism independent from the well known effects on Ca2+ or K+ channels. The inhibition of quantal GABA release can be reduced by an activator of protein kinase C.
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PMID:GABAB receptor-mediated inhibition of tetrodotoxin-resistant GABA release in rodent hippocampal CA1 pyramidal cells. 899 57

Classically, the contiguous epithelial cells show intercellular tight junctions (TJ) positioned as a continuous belt of cell-cell contacts at the boundary of apical and basolateral plasma membranes. Among the epithelia, the "typical" cerebral ependyma is very peculiar due to the absence of TJ, in contrast to the ependyma of the circumventricular organs (e.g. choroid plexus and the subcommissural organ) which shows well differentiated TJ. Since the "typical" ependyma is covered in the rat with a plexus of intraventricular nervous fibres not present at the surface of the circumventricular organs, we hypothesized local repression of TJ by molecules (serotonin, GABA, etc.) released by the supra-ependymal varicosities. Neither the denervation of the "typical" ependyma nor the ex vivo activation of protein kinase C (which increases the transepithelial resistance as it has been reported in other epithelia) produced junctional fibrils as shown by freeze-fracture. As the protein ZO-1 was not detectable in the "typical" ependyma by immunocytochemistry, there is probably repression of the genes responsible for TJ biosynthesis by unidentified endogenous factors.
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PMID:The supra-ependymal innervation is not responsible for the repression of tight junctions in the rat cerebral ependyma. 904 45

Polyclonal antibodies against the N-terminus of the rat rho1 subunit were used to study the distribution of gamma-aminobutyric acid C (GABA(C)) receptors in the cat, goldfish, and chicken retina. Strong punctate immunoreactivity was present in the inner plexiform layer (IPL) of all three species. The punctate labelling suggests a clustering of the GABA(C) receptors at synaptic sites. Weak label was also found in the outer plexiform layer (OPL) and over the cell bodies of bipolar cells. Double immunostaining of vertical sections with an antibody against protein kinase C (PKC) showed the punctate immunofluorescence to colocalize with bipolar cell axon terminals. In the goldfish retina, the axon terminals of Mb1 bipolar cells were enclosed by rho-immunoreactive puncta. In the chicken retina, several distinct strata within the IPL showed a high density of rho-immunoreactive puncta. The results suggest a high degree of sequence homology between the rho subunits of different vertebrate species, and they show that the retinal localization of GABA(C) receptors is similar across different species.
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PMID:Immunocytochemical localization of the GABA(C) receptor rho subunits in the cat, goldfish, and chicken retina. 908 30

Recent evidence indicates that several members of the Na+-coupled transporter family are regulated, and this regulation in part occurs by redistribution of transporters between intracellular locations and the plasma membrane. We elucidate components of this process for both wild-type and mutant GABA transporters (GAT1) expressed in Xenopus oocytes using a combination of uptake assays, immunoblots, and electrophysiological measurements of membrane capacitance, transport-associated currents, and GAT1-specific charge movements. At low GAT1 expression levels, activators of protein kinase C (PKC) induce redistribution of GAT1 from intracellular vesicles to the plasma membrane; at higher GAT1 expression levels, activators of PKC fail to induce this redistribution. However, coinjection of total rat brain mRNA with GAT1 permits PKC-mediated modulation at high transporter expression levels. This effect of brain mRNA on modulation is mimicked by coinjection of syntaxin 1a mRNA and is eliminated by injecting synaptophysin or syntaxin antisense oligonucleotides. Additionally, botulinum toxins, which inactivate proteins involved in vesicle release and recycling, reduce basal GAT1 expression and prevent PKC-induced translocation. Mutant GAT1 proteins, in which most or all of a leucine heptad repeat sequence was removed, display altered basal distribution and lack susceptibility to modulation by PKC, delineating one region of GAT1 necessary for its targeting. Thus, functional regulation of GAT1 in oocytes occurs via components common to transporters and to trafficking in both neural and non-neural cells, and suggests a relationship between factors that control neurotransmitter secretion and the components necessary for neurotransmitter uptake.
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PMID:Second messengers, trafficking-related proteins, and amino acid residues that contribute to the functional regulation of the rat brain GABA transporter GAT1. 909 33

We have previously shown that protein kinase C (PKC) activity is up-regulated in nerve terminals of animals that have been subjected to targeted cellular ablation of cortical and hippocampal neurons by treatment with methylazoxymethanol (MAM), which results in impaired long-term potentiation (LTP) and cognitive deficit. In this study we investigated the consequences of increased membrane-bound PKC in the regulation of release of glutamate, the major excitatory transmitter involved in LTP. We show that nerve terminals of MAM-treated rats show higher PKC activity, as monitored by the in situ phosphorylation of B-50/GAP-43, in both basal and phorbol ester-stimulated conditions. In these animals, hippocampal nerve endings release a greater amount of glutamate than those of controls, both in basal conditions and when synaptosomes are stimulated with KCl or 3,4-diaminopyridine. The potentiation observed in MAM-treated rats was counteracted by the PKC blocker H-7 and the clostridial tetanus toxin. On the contrary, GABA release was not significantly up-regulated, either in basal or in depolarization-evoked conditions. Therefore our data show that the increase in synaptosomal PKC activity is paralleled by increased glutamate but not GABA release in this animal model. Whether this reflects specific up-regulation of membrane PKC activity in glutamatergic terminals or an alteration in the regulation of glutamate release remains to be determined.
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PMID:Increased presynaptic protein kinase C activity and glutamate release in rats with a prenatally induced hippocampal lesion. 910 89

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