Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have investigated the effects of the phorbol ester 12-myristate 13-acetate (PMA) on depolarization-evoked Ca2+ influx and catecholamine secretion in bovine adrenal chromaffin cells. PMA (100 nM) strongly inhibited K(+)-evoked [Ca2+]i transients and Mn2+ quenching of fura-2 fluorescence. In contrast, 4 alpha-phorbol 12,13-didecanoate, a phorbol ester inactive on protein kinase C (PKC), had no effect. Maximal PMA-mediated inhibition occurred at 5-10 min incubations and were variable from cell to cell, ranging from 25 to 65% of controls. The [Ca2+]i transients evoked by the L-type Ca2+ channel activator Bay K 8644 were strongly inhibited by 100 nM PMA. PMA (0.1-10 microM) inhibited K(+)-evoked adrenaline and noradrenaline release by 23-44%. The data indicate that phorbol ester-mediated activation of PKC inhibits voltage-sensitive Ca2+ channels in chromaffin cells, leading to a prominent depression of depolarization-evoked catecholamine secretion.
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PMID:Protein kinase C activator inhibits voltage-sensitive Ca2+ channels and catecholamine secretion in adrenal chromaffin cells. 786 86

Activity-dependent long-lasting plasticity in hippocampus and neocortex includes long-term potentiation (LTP) and long-term depression (LTD) of synaptic strength. Recent studies have confirmed theoretical predictions that the sensitivity of LTP- and LTD-inducing mechanisms is dynamically regulated by previous synaptic history. In particular, prior induction of either repeated short-term potentiations or LTP lowers the threshold for induction of LTD and raises the threshold for LTP. In the current study, transient activation of protein kinase C with phorbol 12,13-diacetate was able to substitute for synaptic activity in priming synapses to exhibit enhanced homosynaptic LTD and to suppress the induction of LTP at Schaffer collateral synapses in area CA1 of hippocampal slices. This priming lasted 30 min, but not 3 hr, following phorbol 12,13-diacetate bath application. These data suggest that a protein kinase C-sensitive phosphorylation site may be an activity-sensitive target mediating the rapid expression of LTP and LTD.
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PMID:Transient protein kinase C activation primes long-term depression and suppresses long-term potentiation of synaptic transmission in hippocampus. 787 48

1. Whole cell voltage-clamp techniques were used in the CA1 region of rat hippocampal slices to study presynaptic and postsynaptic gamma-aminobutyric acid B (GABAB) response mechanisms. The effects of the protein kinase C activator phorbol 12,13-diacetate (PDA), barium (Ba2+), and pertussis toxin were compared on the presynaptic and postsynaptic GABAB actions of bath-applied baclofen and paired-pulse depression (PPD) of the monosynaptic GABAA inhibitory postsynaptic current (IPSC). The magnitude of PPD was dependent on the amplitude of the first response. PPD was predominantly a GABAB-mediated effect, as it was very much reduced by the GABAB antagonist CGP 35348. 2. PDA enhanced monosynaptic GABAA IPSCs through an apparently presynaptic mechanism. Iontophoretic GABAA responses were unaffected, and there was no change in EIPSC. PDA increased the frequency of spontaneous, tetrodotoxin-insensitive IPSCs without significantly affecting their amplitudes. The inactive phorbol ester, 4 alpha-PDA did not alter IPSCs. After PDA application, stimulus intensity was adjusted to produce responses of comparable amplitude to control responses. PDA had a marked and reversible depressant effect on the postsynaptic GABAB response and caused a lesser, but still significant, reduction in the baclofen-induced reduction of monosynaptic IPSCs. PDA had no effect on PPD. 3. Ba2+ dramatically reduced postsynaptic GABAB responses; it had no effect on PPD. Ba2+ tended to decrease the presynaptic baclofen reduction of IPSCs, although this was not statistically significant. 4. Pertussis toxin, injected 2-3 days earlier into the intact hippocampus, blocked all three GABAB responses equally (approximately 70% decrease). 5. We conclude that presynaptic and postsynaptic GABAB mechanisms are mediated by G proteins that couple to different mechanisms. Discrepancies with previous work are evidently due to the use of different tissue preparations and different target responses. Even though protein kinase C activation caused a partial reduction in the presynaptic effect of baclofen, its lack of effect on PPD makes a significant role for protein kinase C in modulation of PPD unlikely.
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PMID:Differences between presynaptic and postsynaptic GABAB mechanisms in rat hippocampal pyramidal cells. 788 61

Whole-cell patch-clamp recordings of evoked excitatory postsynaptic currents (EPSCs) were made from granule cells of the rat dentate gyrus in vitro. Tetanic stimulation in control media evoked a statistically identical long-term potentiation (LTP) of both the AMPA and NMDA receptor-mediated components of the dual component EPSC (AM-PAR and NMDAR EPSCs), as shown by a similar percentage increase in both components when measured at a holding potential of -30 mV, and also by an identical time course of the pre- and post-LTP induced EPSC at -30 mV and -70 mV. Application of the selective metabotropic glutamate receptor (mGluR) agonist 1S,3R-ACPD induced a transient depression followed by a rapid onset LTP of both the AMPAR and the NMDAR components of the dual component EPSC. The ACPD- and tetanically induced LTP of the AMPAR EPSC was NMDAR dependent, being abolished by the NMDAR antagonist AP5. Tetanic stimulation, and application of ACPD, also induced a relatively rapid onset LTP of the pharmacologically isolated NMDAR EPSC. Such tetanically and ACPD-induced LTP of the isolated NMDAR EPSC was also dependent on NMDAR activation, being strongly inhibited by AP5. The tetanically and the ACPD-induced LTP of the NMDAR EPSC were dependent on protein kinase C (PKC) stimulation, being strongly inhibited by the PKC inhibitor PKCI (19-31). The studies suggest that coactivation of the mGluR and NMDAR are required for induction of LTP of both the AMPAR- and NMDAR-mediated synaptic transmission. Moreover, LTP of the NMDAR-mediated synaptic transmission appears to be dependent on coincident activation of the NMDAR and mGluR.
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PMID:Tetanically induced LTP involves a similar increase in the AMPA and NMDA receptor components of the excitatory postsynaptic current: investigations of the involvement of mGlu receptors. 789 Nov 48

Currents elicited by activation of GABAA, glycine (GLY) and glutamate (GLU) receptors (R) in pyramidal neurons of CA1 region from thin slices of rat hippocampus were studied using the tight-seal whole-cell recording techniques. GLU (100 mM) induced a long-lasting depression of GABA- and GLY-activated currents (IGABA and IGLY) when using standard saline in conjunction with depolarization. The long-lasting depression was not observed: (1) in neurons held at -70 mV during GLU application; (2) in neurons depolarized by current injection but not exposed to GLU; (3) when GLU/depolarization protocol was performed in Ca(2+)-free medium; or (4) by using recording patch-pipettes filled with a medium that tightly controlled cytosolic Ca2+ transients. Sphingosine (10 mM), staurosporine (1 mM) and the specific inhibitor of protein kinase C (PKC(19-36) (200 mM in the patch-pipette solution), blocked the long-lasting depression of IGABA. IGABA was depressed even when the treatment with GLU was performed before patch-clamping the neuron. We conclude that the sustained IGABA and IGLY depression is mediated by cytosolic events triggered by the activation of GLUR.
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PMID:Inhibition of GABA and glycine responses by glutamate in rat hippocampal neurons. 790 83

An Aplysia motor neuron cocultured with a single presynaptic sensory neuron exhibits spontaneous miniature EPSPs or EPSCs ("minis") that can be used to assay the release process directly, independent of the presynaptic action potential. Sensory-motor synapses in culture undergo homosynaptic depression with low frequency stimulation (< 1 Hz) and posttetanic potentiation (PTP) with high-frequency stimulation (20 Hz) much as they do in intact ganglia, except that PTP does not occur in culture when sensory neurons are impaled. We measured spontaneous release during each of these two forms of homosynaptic plasticity as a way of testing whether they involve depletion or mobilization of synaptic vesicles (Gingrich and Byrne, 1985). We find that PTP is accompanied by an increase in mini frequency that decays with a time course parallel to the decay of evoked EPSP facilitation. In contrast, depression is not paralleled by a reduction of mini frequency, although extensive stimulation reduces mini frequency for a brief period immediately following stimulation. Neither form of plasticity altered miniature EPSP or miniature EPSC amplitude, corroborating previous evidence that both are presynaptically mediated. These findings suggest that PTP is mediated by a presynaptic mechanism independent of the action potential, such as vesicle mobilization. This presumably Ca(2+)-dependent mechanism does not involve protein kinase C, since we found that the inhibitor H7 does not specifically block PTP. In contrast to PTP, depression appears to involve changes unique to excitation-secretion coupling, such as reduced Ca2+ influx during the action potential (Klein et al., 1980).
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PMID:Modulation of spontaneous transmitter release during depression and posttetanic potentiation of Aplysia sensory-motor neuron synapses isolated in culture. 791 Feb 6

Isolated tissues from the land snail Otala lactea were used to examine the relationship between protein kinase activity and phosphorylation-induced changes associated with metabolic depression. Hepatopancreas and foot muscle were removed from active and estivating land snails and incubated in vitro under aerobic and anoxic conditions. Pyruvate kinase (PK), cAMP-dependent protein kinase (PKA), and protein kinase second messenger compounds (cyclic AMP and inositol 1,4,5-triphosphate) were measured after incubating the tissues for 4 hours. Pyruvate kinase from the hepatopancreas of active snails was phosphorylated during anoxic incubations as indicated by changes in the I50 value for L-alanine. However, measurements of PKA activity and of cellular cAMP concentrations suggested that PKA activity was lower in these incubated tissues. When foot muscle was used as the tissue source, incubation under anoxic conditions produced no changes in PK activity even though PKA activity was drastically reduced. Analysis of changes in inositol 1,4,5-triphosphate concentrations after tissue incubation showed that they were not consistent with changes in PK activity in either organ. These results suggest that PKA and Ca2+/phospholipid-dependent protein kinase C do not phosphorylate PK during anoxia in land snails. The differences between values measured in incubated tissues and those measured in vivo suggest that isolated O. lactea tissues are not a good in vitro model system for studying metabolic changes associated with depressed metabolism.
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PMID:Metabolic depression in land snails: in vitro analysis of protein kinase involvement in pyruvate kinase control in isolated Otala lactea tissues. 793 Nov 23

In model membranes, arachidonic acid and diacylglycerol have been proposed to synergistically induce a membrane-inserted, constitutively active form of protein kinase C. We have investigated the effects of these lipid protein kinase C activators on synaptic efficacy in the Schaffer collateral input to CA1 hippocampal pyramidal cells. Arachidonic acid (5 microM) perfusion combined with repetitive afferent stimulation had no consistent effect on field excitatory postsynaptic potentials recorded in stratum radiatum, while treatment with a cell-permeable diglyceride, oleoyl-acetylglycerol (5 micrograms/ml), followed by stimulation, led to a short-term potentiation. By contrast, the combination of oleoyl-acetylglycerol and arachidonic acid gave rise to a long-lasting non-decremental potentiation of field excitatory postsynaptic potentials. The induction of potentiation was "activity dependent", as there was either no significant effect or there was a measurable depression when repetitive synaptic stimulation was omitted. Furthermore, consistent with a protein kinase C-dependent process, the potentiation was blocked by the kinase inhibitors H-7 and staurosporine. The results suggest that relatively low concentrations of arachidonic acid and diacylglycerol work synergistically through protein kinase C to persistently enhance synaptic transmission. This synergy has the makings of an associative (Hebbian) device for long-term potentiation induction operating at the second messenger level.
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PMID:Arachidonic acid and diacylglycerol ACT synergistically through protein kinase C to persistently enhance synaptic transmission in the hippocampus. 793 99

In isolated human platelets, exposure of subfraction 3 high-density lipoprotein (HDL3) binding sites to high concentrations of HDL3 (1 mg/mL) causes rapid desensitization of HDL3 (50 micrograms/mL)-stimulated breakdown of phosphatidylcholine, as shown in approximately a 70% depression of the maximal 1,2-diacylglycerol release activity by phospholipase C. This desensitization is HDL3 dose dependent (IC50, 150 +/- 20 micrograms/mL, n = 6) and time dependent (t1/2, < 30 seconds). It requires the binding of HDL3, as pretreatment of HDL3 by tetranitromethane does not cause the desensitization of HDL3-induced phospholipase C activity. Permeabilization of human platelets with 10 micrograms/mL digitonin, used to permit access of charged inhibitors to the cytosol, does not interfere with the pattern of HDL3 (1 mg/mL)-induced desensitization of HDL3 (50 micrograms/mL)-stimulated phospholipase C. Inhibitors of protein kinase C (100 mumol/L H-7 and 10 mumol/L staurosporine) markedly inhibit desensitization of HDL3-induced phospholipase C activity, whereas cAMP-dependent protein kinase inhibitor (1 mumol/L), heparin (100 nmol/L), or concanavalin A (0.25 mg/mL) were ineffective. HDL3-induced desensitization is accompanied at least by the phosphorylation of the 94- and 110-kD proteins. Inhibition of HDL3-induced desensitization by 100 mumol/L H-7 or 10 mumol/L staurosporine is characterized by a marked reduction of the phosphorylation state of these proteins in permeabilized platelets. Whereas protein kinase C inhibitors fully inhibited the phosphorylation of the 94- and 110-kD proteins, inhibitors of protein kinase A were less effective. These data establish that phosphorylation by protein kinase C represent a step in the desensitization of HDL3 binding sites in human platelets.
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PMID:Protein kinase C-dependent desensitization of HDL3-activated phospholipase C in human platelets. 804 94

The activities of protein kinase C, total, Mg2 and Na+, K(+)-dependent ATPases in red cell membranes were compared in 46 patients with insulin independent, 30 ones with insulin dependent diabetes mellitus with various degrees of vascular disorders, and in 17 patients with atherosclerosis with the predominant involvement of the main vessels of the lower limbs. Diabetes mellitus and the progress of vascular disorders were associated with a more marked depression of protein kinase C, total and Na+, K(+)-dependent ATPase activities, this being particularly characteristic of the patients with insulin-independent diabetes and macrovascular disorders. Inhibited activities of protein kinase C and ATPases in red cell membranes in the course of diabetic vascular disorders progress evidence their contribution to the pathogenesis of diabetic angiopathy.
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PMID:[Activity of membrane-bound protein kinase C and ATPase in erythrocytes in diabetic angiopathy]. 805 53


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