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)

The effects of phorbol 12-myristate 13-acetate (PMA) on carbamylcholine (CBC)-induced [3H]cyclic GMP formation in mouse neuroblastoma cells (clone N1E-115) were studied. PMA, but not 4 alpha-phorbol, suppressed muscarinic receptor-mediated cyclic GMP responses in a time-dependent and a concentration-dependent fashion with an IC50 of 68.8 +/- 20.2 nM. The inhibitory effects of PMA on CBC-induced cyclic GMP formation were of a mixed competitive and noncompetitive type, being characterized by a depression of maximal cyclic GMP response to CBC and a significant increase in its EC50. PMA also significantly reduced [3H]cyclic GMP formation induced by histamine, without affecting the responses elicited either by sodium azide or the calcium ionophore A23187. Although the inhibitory effects of PMA on CBC-induced cyclic GMP formation were not reversed by washing, these effects were significantly attenuated by H-7 [1-(5-isoquinolinesulfonyl)-2-methylpiperazine], a protein kinase C inhibitor. PMA had no effect on binding of an antagonist ligand to muscarinic receptors, or on the binding characteristics of CBC to these receptors in intact cells. On the other hand, PMA competed for the specific binding of a labeled phorbol ester in intact cells with a potency similar to that of PMA in inhibiting muscarinic receptor-mediated [3H]cyclic GMP responses.
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PMID:Phorbol ester-induced inhibition of cyclic GMP formation mediated by muscarinic receptors in murine neuroblastoma cells. 303 12

In patch-clamped Purkinje cells (PCs), bath application of the ionotropic glutamate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) prevents induction of long-term depression (LTD) of parallel fibre (PF)-mediated EPSPs by a pairing protocol between Ca2+ spike firing and PF stimulation whereas bath application of (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG), a metabotropic glutamate (mGLU) receptor antagonist, does not. On the other hand, LTD can be also induced by pairing direct depolarization of PCs with activation of mGLU receptors by 1S,3R-aminocyclopentyl-dicarboxylate (1S,3R-ACPD), even in the presence of CNQX. In this case, LTD induction is not consistently blocked by bath application of the nitric oxide synthase inhibitor, NG-methyl-L-arginine (L-NMMA), whereas it is strongly blocked when the protein kinase C inhibitor peptide 19-36 is dialysed into PCs. These results are at variance with LTD induced by a pairing protocol between Ca2+ spikes and PF-mediated EPSPs which depends to the same extent on both cascades. Finally, thapsigargin, which depletes most intracellular Ca2+ pools, does not block induction of LTD by a pairing protocol between Ca2+ spikes and PF-mediated EPSPs whereas it prevents the induction of LTD depending on strong mGLU receptor activation.
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PMID:Receptors and second messengers involved in long-term depression in rat cerebellar slices in vitro: a reappraisal. 771 36

Previously the plasma membrane-bound or purified Ca(2+)-translocation ATPase (Ca2+ pump) was found to be activated and phosphorylated by protein kinase C in vitro (K. K. W. Wang et al. 1991, J. Biol. Chem. 266, 9078-9085). We now show that in intact human erythrocytes phorbol-12-myristate 13-acetate (PMA), a known stimulator of protein kinase C, decreases the amplitude of the intracellular calcium ([Ca2+]i) transient induced by 2.5 microM CaCl2 and 10 microM A23187. Since PMA did not affect Ca2+ influx, the decrease in amplitude was most likely due to the stimulation of the Ca2+ pump, the major mechanism of calcium extrusion in these cells. The effect was dose-dependent, the maximum decrease in amplitude (33%) occurring at 1 microM PMA. The depression of the [Ca2+]i transient was further enhanced by the phosphatase inhibitor okadaic acid. It was reversed by the protein kinase C inhibitor staurosporine and could not be mimicked by inactive PMA analogues. In erythrocytes labeled with [32P]orthophosphate, PMA treatment phosphorylated the Ca(2+)-ATPase in a dose-dependent manner. The phosphorylation was inhibited by staurosporine and was slightly enhanced by okadaic acid. Changes in lipid phosphorylation and content were studied under the same conditions in intact cells. The turnover of 32P and lipid phosphate in phosphatidylinositol 4,5-bisphosphate (PIP2) was inhibited by 1 mM adriamycin, concomitant with an increased amplitude of the [Ca2+]i transient. The PIP2 content and its 32P radioactive did not, however, change with PMA stimulation. We conclude that while both protein kinase C and polyphosphoinositides are regulators of Ca(2+)-ATPase activity in the intact human erythrocyte, stimulation of the enzyme activity by PMA is predominantly protein kinase C-mediated.
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PMID:Regulation of the activity and phosphorylation of the plasma membrane Ca(2+)-ATPase by protein kinase C in intact human erythrocytes. 821 16

Stress, such as heat-shock, hypoxia and hypoglycemia, inhibits the initiation of protein synthesis. The effects of heat-shock on protein synthesis, eucaryotic initiation factor 2 (eIF-2) activity, protein kinase C (PKC), and casein kinase II (CKII) activities were studied in primary cortical neuronal cultures. In neurons exposed to heat-shock at 44 degrees C for 20 min, protein synthesis is inhibited by more than 80%, and is accompanied by a 60% decrease in eIF-2 activity. Steady state PKC and CK II activities were not affected by heat-shock. Vanadate (200 microM), a protein phosphotyrosine phosphatase inhibitor, partially prevented the depression of eIF-2 activity during heat-shock, and increased CKII activity by 90%. In contrast, staurosporine (62nM), a protein kinase C inhibitor, did not affect eIF-2 activity. We conclude that heat-shock causes a change in the phosphorylation/dephosphorylation of regulatory proteins leading to a depressed eIF-2 activity and protein synthesis in neurons.
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PMID:Heat-shock inhibits protein synthesis and eIF-2 activity in cultured cortical neurons. 823 16

Synapses made by Aplysia sensory neurons onto motor- and interneuron followers in the intact nervous system exhibit an associative form of synaptic facilitation that is thought to contribute to classical conditioning of the animal's gill and siphon withdrawal reflex (Hawkins et al., 1983; Walters and Byrne, 1983). Here we demonstrate that a similar associative facilitation can be induced between individual sensory and motor neurons isolated in culture. Pairing tetanic stimulation with either of two facilitatory transmitters, 5-HT or small cardioactive peptide, considerably prolongs facilitation compared to either tetanus or transmitter alone. When corrected for the depression that occurs simply in response to low-frequency testing, the facilitation produced by one pairing trial does not decay for more than 20 min after training. This facilitation requires the temporal pairing (0.5 sec forward interstimulus interval) of the two stimuli, tetanus and 5-HT. Delivering the same two stimuli in an unpaired fashion (1 min forward interval) fails to produce the long-lasting effect. Measurements of spontaneous transmitter release during either paired or unpaired training reveal no changes in unitary mEPSP or mEPSC ("mini") amplitude, indicating that the facilitation involves a presynaptic mechanism. While both forms of training dramatically increase the initial frequency of spontaneous release, mini frequency does not remain elevated as long as the evoked EPSP following paired training, nor does paired training specifically enhance spontaneous release frequency. Pairing-specific facilitation was not blocked by the protein kinase C inhibitor H7. In contrast, the same training procedure produced pairing-specific increases of sensory neuron excitability and action potential width, suggesting that cAMP-mediated processes are involved in the paired effect. Although Ca2+ influx is necessary for the associative effect (Abrams, 1985), we find that the facilitation does not require influx through L-type voltage-gated Ca2+ channels, since the effect was not blocked by the dihydropyridine antagonist nitrendipine. Together, these findings indicate that the mechanism underlying associative, activity-dependent facilitation is intrinsic to the sensory neuron synapse, that it is presynaptically mediated by processes unique to evoked synaptic transmission, and that it appears to involve a pairing-specific broadening of the presynaptic action potential, allowing enhanced Ca2+ influx through the dihydropyridine-insensitive channels responsible for release.
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PMID:Pairing-specific, activity-dependent presynaptic facilitation at Aplysia sensory-motor neuron synapses in isolated cell culture. 828 44

1. We have investigated the effect of various protein kinase A (PKA) inhibitors on the phasic and tonic components of the response to potassium chloride (KCl) in the guinea pig ureter. All experiments were performed in ureters pretreated with capsaicin (10 microM for 15 min) to prevent the release of sensory neuropeptides and in the presence of 1 microM Bay K 8644 to maximize calcium (Ca) entry via voltage-sensitive channels. The addition of 80 mM hypertonic KCl produced maximal shortening of the ureter with distinct phasic and tonic components, the latter further showing a transient and a sustained component. Nifedipine (30 microM for 120 min) totally abolished all the responses to KCl. 2. The selective PKA inhibitor, H89 (10 microM), abolished the tonic response to KCl in about 30 min with minor inhibitory effect on the phasic contraction. This pattern was unchanged when extending the contact time to 120 min. When added 30 min before the next challenge, H89 (1-30 microM) concentration-dependently inhibited the responses to KCl with a preferential inhibitory effect on the tonic contraction. Another PKA inhibitor, H8, produced similar effects at tenfold higher concentrations (10-300 microM) than H89, consistent with the known potency ratio of these isoquinoline derivatives in inhibiting PKA. 3. The potent and nonselective protein kinase inhibitor, staurosporine (10-100 nM) produced an even depression of the various phases of the response to KCl. The selective protein kinase G inhibitor, KT 5823 (10 microM for 60 min) produced only a slight reduction of the sustained tonic response to KCl. The selective protein kinase C inhibitor GF 109,203X (1-3 microM) and the cAMP analog, Rp-cAMPS (300 microM for 60 min) had no effect on the three components of the response to KCl. 4. In the presence of Bay K 8644, electrical field stimulation (10 Hz for 1 sec, 60 V, pulse width 5 ms) produces direct myogenic phasic contractions (twitches) of the ureter which are suppressed by nifedipine (10-30 microM). H8 (up to 30 microM) and H89 (up to 300 microM) had minor effect on the amplitude of twitches, consistent with their poor inhibitory activity on the phasic responses to KCl. 5. In sucrose gap, superfusion with 80 mM hypertonic KCl produced action potentials followed by a sustained depolarization of the membrane: the two electrical responses underlie the phasic and tonic components of contraction to KCl, respectively. H89 (10 microM for 30 min) did not affect the resting membrane potential nor the KCl-evoked action potentials and sustained depolarization. H89 had no effect on the phasic contraction to KCl but markedly depressed (about 65% inhibition) the tonic contraction. 6. The present findings are consistent with the view that phosphorylation by PKA increases the availability of L-type Ca channels in the ureter smooth muscle. Blockade of PKA dissociates the electromechanical coupling between the sustained membrane depolarization produced by KCl and the corresponding sustained increase in tension. The L-type Ca channel responsible for generating action potentials and phasic contractions to KCl are less sensitive to PKA inhibitors than those responsible for the tonic contraction.
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PMID:Protein kinase A inhibitors selectively inhibit the tonic contraction of the guinea pig ureter to high potassium. 891 54

Intracellular recordings were obtained from neocortical brain slices of adult rats maintained in vitro. The effect of metabotropic glutamate receptor activation on spike frequency adaptation in regular spiking layer II and III neurons was determined. Putative metabotropic glutamate receptor agonists and antagonists, as well as inhibitors of intracellular signaling systems, were tested. Activation of metabotropic glutamate receptors by bath applied (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (1S,3R-ACPD; 50-200 microM) reduced the first interspike interval and increased action potential frequency at all current intensities. This effect was not blocked by ionotropic glutamate receptor antagonists. Under these recording conditions, quisqualate (1-10 microM) similarly reduced spike frequency adaptation. Neither 1R,3S-ACPD, L-2-carboxycyclopropylglycine-I nor the putative presynaptic metabotropic glutamate receptor agonist, L-2-amino-4-phosphonobutyrate, mimicked the effects of 1S,3R-ACPD or quisqualate. Bath application of the putative metabotropic glutamate receptor antagonist, alpha-methyl-4-carboxyphenylglycine, competitively antagonized the excitatory actions of 1S,3R-ACPD. Another putative antagonist, L-2-amino-3-phosphonopropionate, failed to antagonize the reduction in spike frequency adaptation. Intracellular injection of guanosine-5'-O-(2-thiodiphosphate), a non-hydrolysable analog of GTP, inhibited the postsynaptic metabotropic glutamate receptor-mediated effects. However, the depression of synaptic transmission by 1S,3R-ACPD was not antagonized by this compound. The decrease in spike frequency adaptation by 1S,3R-ACPD was not prevented by prior exposure to the non-specific protein kinase inhibitors H-7 or H-8 (10 microM), the protein kinase A inhibitor H-89 (0.25 microM) or the protein kinase C inhibitor staurosporine (0.10 microM). These data suggest that the metabotropic glutamate receptor-mediated reduction in spike adaptation requires the activation of specific G-protein-coupled metabotropic glutamate receptor subtypes located on postsynaptic sites. The increase in neuronal excitability observed in the adult neocortex may be mediated either by an unidentified G-protein-coupled second messenger or via a membrane-delimited G-protein action.
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PMID:G-protein activation by metabotropic glutamate receptors reduces spike frequency adaptation in neocortical neurons. 892 28

1. The modulation by adenosine of GABA-activated current (IGADA) was studied in freshly isolated rat dorsal root ganglion (DRG) neurons using the whole-cell patch-clamp technique. 2. In most of the DRG neurons examined (68/90, 75.5%) adenosine (1-10 microM) suppressed IGABA, while in some neurons examined, it potentiated (16/90, 17.8%) IGABA. It exerted no effects on IGABA in a few cells (6/90, 6.7%). 3. Adenosine shifted the GABA concentration-response curve downward with no significant change of the EC50. The maximal response to GABA was suppressed by 29.6 +/- 2.6%. The adenosine-induced inhibition of IGABA showed no voltage dependence. 4. 8-Cyclopentyl-1,3-dimethylxanthine (DPCPX; 1 microM), a selective A1 adenosine receptor antagonist, partially reversed adenosine inhibition of IGABA and completely blocked N6-cyclo-hexyladenosine (CHA; an A1 adenosine receptor agonist) inhibition of IGABA. DPCPX (1 microM) also blocked the suppression of IGABA by 2-chloroadenosine (CADO). CGS21680, a selective A2A adenosine receptor agonist, did not inhibit IGABA and DMPX, a selective A2A adenosine receptor antagonist, did not prevent adenosine inhibition of IGABA. 5. Intracellular application of H-7 (20 microM; a protein kinase C inhibitor) reversed adenosine inhibition of IGABA while inclusion of cAMP (1 mM), H-9 (20 microM; a protein kinase A inhibitor) and BAPTA (10 mM; a chelator of calcium ions) in the recording pipette did not affect the depression of IGABA by adenosine. IGABA was also suppressed by internal perfusion of PMA, a protein kinase C activator. 6. The results suggest that adenosine, as a neuromodulator, exerts a modulatory effect on the GABA-induced presynaptic inhibition in primary sensory transmission.
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PMID:Modulation by adenosine of GABA-activated current in rat dorsal root ganglion neurons. 917 95

Long-term depression was established in cerebellar Purkinje cells using 20 pairings of a brief, high frequency train of parallel fiber stimulation with a subsequent 100 ms depolarizing current injection. Effects were assessed on the peak amplitude of Purkinje cell excitatory post synaptic potentials (EPSPs) elicited by single parallel fiber test pulses. Intradendritically recorded Purkinje cell EPSPs exhibited long-term (>20 min) reduction in peak amplitude following paired stimulation but not if pretreated with the protein kinase C inhibitor calphostin C or iontophoretically injected with the calcium chelator EGTA. The similarity of the stimulation protocol and behavioral conditioning paradigms suggests pairing-specific long-term synaptic depression is a valuable model for understanding the cellular mechanisms underlying cerebellar cortical contributions to learning.
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PMID:Pairing-specific long-term depression prevented by blockade of PKC or intracellular Ca2+. 969 6

1. During block of gamma-aminobutyric acid-A-mediated inhibition, low-frequency stimulation (2 Hz, 900 pulses) to Schaffer collateral-CA1 neuron synapses of adult rat hippocampus induced an N-methyl-D-aspartate receptor-independent, postsynaptic Ca2+-dependent depression of synaptic strength (long-term depression; LTD). 2. Ratio imaging with fura-2 revealed moderate dendritic [Ca2+] increases (approximately 500 nM) during only the initial approximately 30 s of the 7.5 min stimulation period. Conditioning for 30 s was, however, insufficient to induce LTD. 3. The [Ca2+] changes were insensitive to the metabotropic glutamate receptor (mGluR) antagonist (+)-alpha-methyl-4-carboxyphenylglycine (MCPG). MCPG, however, completely blocked LTD when present during conditioning. 4. The [Ca2+] changes were abolished by postsynaptic hyperpolarization (-110 mV at the soma). Hyperpolarizing neurons to -110 mV during conditioning significantly attenuated LTD induction. 5. LTD induction was also blocked by the postsynaptic presence of the protein kinase C inhibitor peptide PKC(19-36). 6. These results suggest that LTD induction in adult hippocampus by prolonged low-frequency stimulation depends on both a rapid Ca2+ influx through voltage-sensitive channels and synaptic stimulation of mGluRs which may be coupled to phospholipase C.
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PMID:Requirement of rapid Ca2+ entry and synaptic activation of metabotropic glutamate receptors for the induction of long-term depression in adult rat hippocampus. 971 58


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