UMLS:C0011570 - FACTA Search

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Query: UMLS:C0011570 (depression)
172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Long-term potentiation (LTP) and long-term depression (LTD) are persistent modifications of synaptic efficacy that may contribute to information storage in the CA1 region of the hippocampus. Persistently enhanced phosphorylation has been implicated in the maintenance phase of LTP. This hypothesis is supported by our previous observation that protein kinase M zeta (PKM zeta), the constitutively active catalytic fragment of a single protein kinase C isoform (PKC zeta), increases in LTP maintenance. In contrast, dephosphorylation may be important in LTD maintenance, because phosphatase inhibitors reverse established LTD, in addition to blocking its induction. Because phosphorylation is determined by a balance of phosphatases and kinases, both increases in phosphatase activity and decreases in kinase activity could contribute to LTD. We now report that the reduction of protein kinase activity by H7, as well as selective inhibition of PKC by chelerythrine, mimics and occludes the maintenance phase of homosynaptic LTD in rat hippocampal slices. Conversely, saturated LTD occludes the synaptic depression caused by chelerythrine. Biochemical analysis demonstrates a decrease of PKM zeta, as well as PKCs gamma and epsilon, in LTD maintenance and a concomitant loss of constitutive PKC activity. LTD and the downregulation of PKM zeta are prevented by NMDA receptor antagonists and Ca(2+)-dependent protease inhibitors. Both LTD and the downregulation of PKM zeta are reversible by high-frequency afferent stimulation. Our findings indicate that the molecular mechanisms of LTP and LTD maintenance are inversely related through the bidirectional regulation of PKC.
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PMID:Bidirectional regulation of protein kinase M zeta in the maintenance of long-term potentiation and long-term depression. 875 45

The effect of protein kinase C (PKC) activation on 4-aminopyridine (4-AP)-sensitive delayed rectifier current (IdK) was studied in isolated rabbit portal vein smooth muscle cells by use of standard whole cell voltage clamp. The effects of the phorbol ester, 4 beta-phorbol 12,13-dibutyrate (PdBu, 100 nM) and diacylglycerol analogues, 1,2-dioctanoyl-sn-glycerol (1,2-diC8, 10 microM) and 1,3-dioctanoyl-sn-glycerol (1,3-diC8, 10 microM), on macroscopic whole cell IdK were assessed in myocytes dialyzed with 10 mM 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) and 5 mM ATP (20-22 degrees C). Activation of PKC by 1,2-diC8 or PdBu caused a decline in IdK that was reversed with washout of drug. 1,2-diC8 had no effect on outward current present after exposure to 4-AP (20 mM). The inactive analogue, 1,3-diC8, did not affect IdK, but subsequent exposure to the active analogue, 1,2-diC8, caused a marked depression of the current. The inhibition of IdK by 1,2-diC8 was significantly reduced by intracellular dialysis with the inhibitors of PKC, chelerythrine (50 microM) and calphostin C (1 microM). Substitution of extracellular Ca2+ with Mg2+ in the presence of 10 mM intracellular BAPTA did not affect the suppression of IdK by 1,2-diC8, indicating the involvement of a Ca(2+)-independent isoform of PKC. This study suggests a novel signal transduction mechanism for inhibition of 4-AP-sensitive IdK involving a phosphotransferase reaction catalyzed by PKC in vascular smooth muscle myocytes.
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PMID:Protein kinase C inhibits delayed rectifier K+ current in rabbit vascular smooth muscle cells. 876 Jan 65

In cerebellar long-term depression (LTD), conjunctive stimulation of parallel and climbing fiber inputs to a Purkinje neuron (PN) results in a selective depression of parallel fiber-PN synaptic strength. A similar phenomenon may be induced in the cultured PN when glutamate pulses and PN depolarization, which mimic the effects of parallel and climbing fibers, respectively, are coapplied. Here, we show that LTD can be induced in two very reduced preparations of the postsynaptic neuron; an acutely dissociated preparation and a perforated outside-out macropatch of dendritic membrane. LTD in these preparations retains properties of that seen in an intact cultured PN in that it is not induced by either glutamate pulses or depolarization alone and requires calcium influx, mGluR activation, and PKC activation for induction. As both of these preparations lack dendritic spine compartments, these findings suggest that the associative nature of LTD induction does not require this level of morphological organization.
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PMID:Defining a minimal computational unit for cerebellar long-term depression. 878 Jun 56

Activity and distribution of protein kinase C (PKC) in the rat cerebral cortex was correlated with the development of spreading depression. When the 'waves' of the slow potential shift, induced by topical application of concentrated KCl solutions, were allowed to spread over the cerebral cortex for 10 min, both cytosolic and particulate fractions of the enzyme were increased to 169% and 143%, respectively, of the control values obtained from the contralateral, relatively intact hemicortex. When the enzyme activities were correlated with development of a single slow potential shift, it appeared that in the cortical area fully depolarized (under the maximum of negativity), the respective values were 175% and 157%. One min after recovery of the single wave of spreading depression both cytosolic and particulate fractions continued to rise up to 218% and 239%, respectively. During 5 min of recovery both the cytosolic and particulate fractions fell to 71% and 57%, respectively, of control levels. Even at 10 min the cytosolic enzyme was still decreased to 80%. At 20 min no difference between control and experimental values was found (soluble, 111%; particulate, 96%). The results are discussed in the context of data obtained in a few studies dealing with depolarization-induced changes of PKC in vitro.
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PMID:Protein kinase C in the rat cerebral cortex during spreading depression. 878 77

A hypothetical mechanism is proposed for the induction of long-term posttetanic potentiation of the efficiency of inhibitory synaptic transmission (LTPi). The data we have previously obtained have made it possible to hypothesize that modifiable inhibitory synapses are situated on the dendritic spines on which there are metabotropic GABAb receptors. It is hypothesized that modification of inhibitory transmission is determined precisely by these receptors, the activation of which leads to inactivation of protein kinases C and A (PKC and PKA) as a result of a decrease in the intracellular concentration of Ca++ and the inhibition of cAMP. The hypothesis is confirmed by experiments in which it was demonstrated that an effect similar to LTPi took place as a result of the inactivation of PKC and PKA. It is hypothesized that eicanoid [sic] acids may be retrograde messengers during LTPi. A new hypothetical mechanism underlying long-term depression of excitatory transmission (LTDe) is proposed, according to which tetanized afferent fibers must simultaneously monosynaptically excite and disynaptically inhibit one and the same postsynaptic cell. LTDe may be induced only in those pathways which activate [are activated by--unclear from Russian text--Trans.] GABAb receptors. The proposed hypothesis make it possible to explain the results of certain experiments.
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PMID:Activation by GABAb, reduction of the intracellular concentration of Ca++, and inhibition of protein kinases are possible mechanisms of the long-term posttetanic modification of the efficiency of inhibitory transmission in the new cortex. 880 74

Cerebellar long-term depression (LTD) may be reliably induced in the cultured Purkinje neuron when glutamate pulses and Purkinje neuron depolarization are applied together 6 times. When the number of these conjunctive stimuli was reduced to 2, a short-term depression (STD) lasting 20-40 min was induced in 4/12 cells. The enzyme phospholipase A2 cleaves membrane phospholipids causing liberation of free unsaturated fatty acids, which in turn synergistically activate protein kinase C when present with diacylglycerol and Ca. Application of free unsaturated fatty acids with 2 conjunctive stimuli resulted in an apparent conversion of STD cases to LTD. Application of phospholipase A2 inhibitors during 6 conjunctions converted LTD to STD. These findings suggest a model in which liberation of unsaturated fatty acids by phospholipase A2 contributes to a synergistic activation of protein kinase C, the full activation of which results in LTD induction, and the partial activation of which results in STD induction.
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PMID:Phospholipase A2 controls the induction of short-term versus long-term depression in the cerebellar Purkinje neuron in culture. 884 62

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

Three types of ionic current essentially determine the firing pattern of nerve cells: the persistent Na+ current, the M current and the low-voltage-activated Ca(2)+ current. The present article summarizes recent experiments concerned with the basic properties of these currents. Keynes and Meves (Proc R Soc Lond B (1993) 253, 61-68) studied the persistent or steady-state Na+ current on dialysed squid axons and measured the probability of channel opening both for the peak and the steady-state Na+ current (PF(peak) and PF(ss)) as a function of voltage. Whereas PF(peak) starts to rise at -50 mV and reaches a maximum at +40 to +50 mV, PF(ss) only begins to rise appreciably at around 0 mV and is still increasing at +100 mV. This differs from observations on vertebrate excitable tissues where the persistent Na+ current tums on in the threshold region and saturates at around 0 mV. Schmitt and Meves (Pflugers Arch (1993) 425, 134-139) recorded M current, a non-inactivating K+ current, from NGI08-15 neuroblastoma x glioma hybrid cells, voltage-clamped in the whole-cell mode, and studied the effects of phorbol 12,13-dibutyrate (PDB), an activator of protein kinase C (PKC), and arachidonic acid (AA). PDB and AA both decreased I(M), the effective concentrations being 0.1-1 mu M and 5-25 mu M, respectively; while the PDB effect was regularly observed, the M current depression by AA was highly variable from cell to cell. The PKC 19-31 peptide, an effective inhibitor of PKC, in a concentration of 1 muM almost totally prevented the effects of PDB and AA on M current, suggesting that both are mediated by PKC. Schmitt and Meves (Pflugers Arch (1994a) 426, Suppl R 59) measured low-voltage-activated (l-v-a) and high-voltage-activated (h-v-a) Ca2+ currents on NG108-15 cells and investigated the effect of AA and PDB on both types of current. At pulse potentials > -20 mV, AA (25-100 mu M) decreased 1-v-a and h-v-a I(Ca). The decrease was accompanied by a small negative shift and a slight flattening of the activation and inactivation curves of the l-v-a I(Ca). The AA effect was not prevented by 50 mu M eicosa-5,8,11,14-tetraynoic acid (ETYA), an inhibitor of AA metabolism, or PKC 19-31 peptide and not mimicked by 0.1-1 mu M PDB. Probably, AA acts directly on the channel protein or its lipid environment. The physiological relevance of these three sets of observations is briefly discussed.
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PMID:Model experiments on squid axons and NG108-15 mouse neuroblastoma x rat glioma hybrid cells. 886 17

1. The sensorimotor synapse of Aplysia expresses various shortlasting changes in synaptic efficacy including homosynaptic depression (HSD) and heterosynaptic facilitation by serotonin (5-HT) either at nondepressed sensory neuron (SN) synaptic connections or at SN synaptic connections first depressed by HSD. We examined the temporal sequence of expression for these three forms of synaptic plasticity as synaptic connections between SN and target motor cell L7 were reestablished and stabilized in cell culture. The same cultures were reexamined at different time points. 2. We found that only HSD and facilitation of nondepressed synapses were expressed at "mature" levels on day 1 in culture, whereas facilitation of depressed connections was significantly weaker on day 1 than the facilitation evoked on day 4. 3. The late expression of 5-HT facilitation of depressed SN synaptic connections was not a result of a reduced capacity of two kinases activated by 5-HT (protein kinase A and protein kinase C) to evoke facilitation. Direct activation of the kinases with either cyclic AMP or phorbol esters evoked the synaptic facilitation both on day 1 and day 4. 4. The late expression of 5-HT facilitation of depressed SN synaptic connections was correlated with the late functional expression of receptors sensitive to 5-HT antagonists cyproheptidine or methiothepin. Both antagonists significantly interfered with 5-HT facilitation on day 4, but both had little effect on 5-HT facilitation of the same cultures examined on day 1. 5. Unlike the properties of SNs in the intact nervous system, both antagonists reduced significantly the excitability changes evoked by 5-HT when the SNs were plated either alone or with target cell L11 that fails to induce synapse formation. When cultured with L7, however, both antagonists evoked little change in 5-HT excitability. In the presence of L7, the SNs expressed the phenotype more typical of SNs in the intact nervous system. 6. The results suggest that target interactions not only influence the formation of chemical connections but they also may regulate the acquisition of specific plastic properties by the presynaptic neuron including the functional expression of receptors for neuromodulators.
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PMID:Development of short-term heterosynaptic facilitation at aplysia sensorimotor synapses in vitro is accompanied by changes in the functional expression of presynaptic serotonin receptors. 889

1. The effects of substance P (SP) and related tachykinins on the function of gamma-aminobutyric acid-A (GABAA) receptors were examined in acutely dissociated neurones of bullfrog dorsal root ganglia (DRG) by using whole-cell voltage-clamp techniques. 2. Application of SP (10 nM to 1 microM) depressed inward currents produced by GABAA receptor activation (IGABA). Neurokinin A (NKA) and neurokinin B (NKB) also depressed IGABA; the rank order of agonist potency was SP > NKA > NKB. Spantide ([D-Arg1, D-Trp7,9,Leu11]SP) and L-703,606, NK1 receptor antagonists, blocked the SP-induced depression of IGABA. 3. SP irreversibly depressed IGABA, when neurones were intracellularly dialysed with GTP gamma S. Intracellular application of GDP beta S prevented the SP-induced depression of IGABA. Pertussis toxin (PTX) did not block the inhibitory effect of SP on IGABA. 4. The depression of IGABA produced by SP was inhibited by H-7 and PKC(19-36), protein kinase C (PKC) inhibitors, but not by H-9 and HA-1004, protein kinase A inhibitors. IGABA was suppressed by application of sn-1,2-dioctanoyl glycerol (DOG), a PKC activator. 5. It is concluded that activation of neurokinin-1 (NK1) receptors downregulates the function of the GABAA receptor of primary sensory neurones through a PTX-insensitive G-protein. PKC may be involved in the transduction pathway of the tachykinin-induced inhibition of the GABAA receptor.
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PMID:Substance P suppresses GABAA receptor function via protein kinase C in primary sensory neurones of bullfrogs. 891 Feb 28

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