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)

Calmodulin-dependent phosphodiesterase (CaM-PDE) is selectively expressed in specific neuronal populations in adult rat brain. In cerebellar cortex, it is expressed at high levels in Purkinje cells (soma and dendrites). Climbing fiber ablation by intraperitoneal injections of 3-acetylpyridine resulted in a selective depression of cerebellar CaM-PDE expression using Western immunoblot procedures; neither calcineurin (calmodulin-dependent protein phosphatase) nor other calmodulin binding proteins, detected by biotinylated calmodulin overlays, were affected. Immunocytochemical staining of cerebellum revealed a loss of detectable CaM-PDE immunoreactivity in Purkinje cells, with no appreciable change in calcineurin immunoreactivity. Cerebral cortex was examined as a control for a direct effect of 3-acetylpyridine on CaM-PDE expression, independent of climbing fiber deafferentation. There were no detectable changes in CaM-PDE or calcineurin immunoreactivity in cortical pyramidal cells, and no changes were detected, either in Western blot analyses for CaM-PDE or calcineurin or in biotinylated calmodulin overlays. These data suggest that CaM-PDE expression in Purkinje cells is regulated transsynaptically by climbing fiber inputs.
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PMID:Evidence for transsynaptic regulation of calmodulin-dependent cyclic nucleotide phosphodiesterase in cerebellar Purkinje cells. 274 32

Long-term potentiation (LTP) is a synaptic mechanism thought to be involved in learning and memory. Long-term depression (LTD), an activity-dependent decrease in synaptic efficacy, may be an equally important mechanism which permits neural networks to store information more effectively. One form of LTD that has been observed in the hippocampus requires activation of postsynaptic NMDA (N-methyl-D-aspartate) receptors, a change in postsynaptic calcium concentration, and activation of postsynaptic serine/threonine protein phosphatase 1 (PP1) or 2A (PP2A). The mechanism by which PP1 or PP2A is regulated by synaptic activity is unclear because these protein phosphatases are not directly influenced by calcium concentration. LTD induction may require activation of a more complex protein phosphatase cascade consisting of the Ca2+/calmodulin-dependent protein phosphatase, calcineurin, its phosphoprotein substrate, inhibitor-1, and PP1. We tested this hypothesis using calcineurin inhibitors as well as different forms of inhibitor-1 loaded into postsynaptic cells. Our results suggest a signalling pathway in which calcineurin dephosphorylates and inactivates inhibitor-1. This in turn increases PP1 activity and contributes to the generation of LTD.
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PMID:Involvement of a calcineurin/inhibitor-1 phosphatase cascade in hippocampal long-term depression. 751 79

Long-term depression (LTD) of synaptic transmission, often used as an essential component in synaptic models for learning, memory and forgetting, can be produced in layer II/III of the visual cortex by a prolonged, low-frequency stimulation (LFS) of layer IV. The activation of Ca2+/calmodulin-dependent protein phosphatase, calcineurin, has been postulated to play a role in the induction of LTD. The recent introduction of a specific inhibitor for calcineurin, FK506, prompted the investigation of the involvement of this phosphatase in the induction of LTD in visual cortex. Thus, we administered FK506 at 1 microM to visual cortical slices of young rats, and found that it did not significantly affect field responses of layer II/III evoked by test stimulation of layer IV at 0.1 Hz, but prevented LTD of the responses from being induced by LFS (1 Hz for 15 min) in all the 10 slices tested. Without FK506, significant LTD was induced by the same parameters of LFS in 8 of the 12 slices. These results suggest the critical involvement of calcineurin in producing LTD in visual cortex.
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PMID:An inhibitor for calcineurin, FK506, blocks induction of long-term depression in rat visual cortex. 753 57

1. Activation of human D2(s) dopamine receptors with quinpirole (10 nM) inhibits omega-conotoxin GVIa-sensitive, high-threshold calcium currents when expressed in differentiated NG108-15 cells (55% inhibition at +10 mV). This inhibition was made irreversible following intracellular dialysis with the non-hydrolysable guanosine triphosphate analogue GTP-gamma-S (100 microM), and was prevented by pretreatment with pertussis toxin (1 microgram ml-1 for 24 h). 2. Stimulation of protein kinase C with the diacylglycerol analogue, 1-oleoyl-2-acetyl-sn-glycerol (100 microM), also attenuated the inhibition of the sustained calcium current but did not affect the receptor-mediated decrease in rate of current activation. Similarly, okadaic acid (100 nM), a protein phosphatase 1/2A inhibitor, selectively occluded the inhibition of the sustained current. 3. The depression of calcium currents by quinpirole (10 nM) was enhanced following intracellular dialysis with 100 microM cyclic adenosine monophosphate (cyclic AMP, 72.8 +/- 9.8% depression), but was not mimicked by the membrane permeant cyclic GMP analogue, Sp-8-bromoguanosine-3',5':cyclic monophosphorothioate (100 microM). 4. Inhibition of calcium currents was only partly attenuated by 100 ms depolarizing prepulses to +100 mV immediately preceding the test pulse. However, following occlusion of the sustained depression with okadaic acid (100 nM) the residual kinetic slowing was reversed in a voltage-dependent manner (P < 0.05). 5. Thus pertussis toxin-sensitive G-proteins liberated upon activation of human D2(short) dopamine receptors inhibited high-threshold calcium currents in two distinct ways. The decrease in rate of calcium current activation involved a voltage-dependent pathway, whereas the sustained inhibition of calcium current involved, in part, the voltage-resistant phosphorylation by cyclic AMP-dependent protein kinases and subsequent dephosphorylation by protein phosphatases 1/2A.
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PMID:Phosphorylation- and voltage-dependent inhibition of neuronal calcium currents by activation of human D2(short) dopamine receptors. 758 57

The influence of internal Ca2+ ions has been investigated during intracellular perfusion of isolated neurones from pedal ganglia of Helix pomatia in which serotonin (5-HT) induces a cyclic-adenosine-monophosphate-(cAMP)-dependent enhancement of high-threshold Ca2+ current (ICa). Internal free Ca2+ ([Ca2+]i) was varied between 0.01 and 10 microM by addition of Ca(2+)-EGTA [ethylenebis(oxonitrilo)tetraacetate] buffer. Elevation of [Ca2+]i depressed the 5-HT effect. The dose/effect curve for the Ca2+ blockade had a biphasic character and could be described by the sum of two Langmuir's isotherms for tetramolecular binding with dissociation constants Kd1 = 0.063 microM and Kd2 = 1 microM. Addition of calmodulin (CM) antagonists (50 microM trifluoperazine or 50 microM chlorpromazine), phosphodiesterase (PDE) antagonists [100 microM isobutylmethylxanthine (IBMX) or 5 mM theophylline] and protein phosphatase antagonists [2 microM okadaic acid (OA)] in the perfusion solution caused "anticalcium" action and modified the Ca2+ binding isotherm. Using the effect of OA and IBMX, two components of the total Ca2+ inhibition were separated and evaluated. In the presence of one of these blockers tetramolecular curves with Kd1 = 0.04 microM and Kd2 = 0.69 microM were obtained describing the activation of the retained unblocked enzyme--PDE or calcineurin (CN) correspondingly. The sum of these isotherms gave a biphasic curve similar to that in control. Leupeptin (100 microM), a blocker of Ca(2+)-dependent proteases did not influence the amplitude of 5-HT effect, indicating that channel proteolysis is not involved in the depression. Our findings show that the molecular mechanism of Ca(2+)-induced suppression of the cAMP-dependent upregulation of Ca2+ channels is due to involvement of two Ca(2+)-CM-dependent enzymes: PDE reducing the cAMP level, and CN causing channel dephosphorylation. No other processes are involved in the investigated phenomenon at a Ca2+ concentration of less than or equal to 10 microM.
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PMID:Mechanisms of antagonistic action of internal Ca2+ on serotonin-induced potentiation of Ca2+ currents in Helix neurones. 768 96

The frequency-dependent long-term modifications of pharmacologically isolated N-methyl-D-aspartate (NMDA) receptor-mediated excitatory postsynaptic potential (EPSPNMDA) was studied. Intracellular recordings were obtained from CA1 cells of rat hippocampal slices and in the presence of 6-cyano-7-nitroquinoxaline-2,3-dione (10 microM) and bicuculline (20 microM) which block non-NMDA and GABAA receptors, respectively. Low-frequency stimulation at 5 Hz resulted in a long-term depression (LTD) of EPSPNMDA in 12 of 17 cells. However, when the stimulus frequency was increased to 30 Hz, a long-term potentiation (LTP) of EPSPNMDA was observed in 7 out of 9 cells. The LTD was not affected by pretreating the slices with okadaic acid (0.5-1 microM) suggesting that activation of endogenous protein phosphatase is not responsible for this process. In the presence of L-2-amino-3-phosphonopropionic acid (50 microM) or (RS)-alpha-methyl-4-carboxyphenylglycine (200 microM), 5 Hz tetanization resulted in LTP instead of LTD. These results suggest that activation of metabotropic glutamate receptor (mGluR) is necessary for the induction of EPSPNMDA LTD and blockade of mGluR unmasks a LTP.
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PMID:The involvement of metabotropic glutamate receptors in long-term depression of N-methyl-D-aspartate receptor-mediated synaptic potential in the rat hippocampus. 775 92

In order to investigate phosphorylation-dephosphorylation processes underlying long-term depression (LTD) in cerebellar Purkinje cells, the protein phosphatase inhibitors calyculin A and microcystein-LR were applied to Purkinje cells in guinea pig cerebellar slices either by bath application or by intracellular pressure injection. Under the influence of these protein phosphatase inhibitors, excitatory post-synaptic potentials evoked by stimulation of parallel fibres exhibited marked depression which developed at a rate dependent on the rate of parallel fibre stimulation. The protein phosphatase inhibitors thus substitute climbing fibre signals which induce LTD when combined with parallel fibre signals. Peculiarly, this is opposite to the effect in pyramidal cells, where protein phosphatase inhibitors block LTD.
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PMID:A unique role of protein phosphatases in cerebellar long-term depression. 775 14

While there is considerable evidence that protein kinase activity is involved in memory formation, there has been, as yet, no direct investigation of a role for protein phosphatases. However, phosphatases have been implicated in the effects of the activation of glutamate receptors of the NMDA type, in long-term depression, and in the regulation of transmitter release and membrane ion channel activities, phenomena which have been shown to be possibly involved in cellular memorial processes. In the present paper, inhibition of protein phosphatase by 0.5 nM okadaic acid, a selective inhibitor of phosphatases 1 and 2A, is demonstrated to prevent memory consolidation in day-old chicks trained on a single trial passive avoidance task. Retention losses first occurred after 30 min post-learning, at an intermediate stage of memory formation preceding a protein synthesis-dependent long-term stage. It is suggested that protein phosphatase activity is involved in precursor processes to long-term memory consolidation.
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PMID:The impairment of long-term memory formation by the phosphatase inhibitor okadaic acid. 775 89

1. Ca(2+)-activated K+ channels regulate the excitability of many nerve terminals. A Ca(2+)-activated K+ channel present in the membranes of rat posterior pituitary nerve terminals runs down following the formation of excised patches. This run-down process reflects enzymatic dephosphorylation. 2. Both Mg-ATP and the protein phosphatase inhibitor okadaic acid prevented run-down of channel activity in excised patches. The okadaic acid sensitivity suggests that run-down resulted from dephosphorylation by a type 1 protein phosphatase. 3. Guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) accelerated run-down by accelerating okadaic acid-sensitive dephosphorylation. GTP gamma S had no effect on the activity of the protein kinase in these patches. These results suggest a direct coupling between a G-protein and a protein phosphatase. 4. After run-down, channel activity could be restored by Mg-ATP; restoration depended on ATP hydrolysis, but did not require Ca2+ or a second messenger. Restoration of channel activity by ATP was blocked by staurosporine and 1-(5-isoquinolinylsulphonyl)-3-methylpiperizine, but not by more specific inhibitors of protein kinases. 5. Restoration of channel activity by phosphorylation was very sensitive to membrane potential; increasing the voltage by as little as 10 mV could dramatically enhance recovery. 6. Ca2+ and voltage acted synergistically to enhance phosphorylation; higher [Ca2+] permitted phosphorylation at more negative potentials. 7. During trains of high frequency stimulation under current clamp, action potentials were influenced by both the protein phosphatase and protein kinase, indicating that enzymatic modulation of channel gating occurs under physiological conditions. An important implication of these results is that voltage-dependent phosphorylation could play a role in use-dependent depression of secretion from nerve terminals.
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PMID:Phosphorylation and dephosphorylation modulate a Ca(2+)-activated K+ channel in rat peptidergic nerve terminals. 802 31

The effectiveness of long-term potentiation (LTP) as a mechanism for information storage would be severely limited if processes that decrease synaptic strength did not also exist. In area CA1 of the rat hippocampus, prolonged periods of low-frequency afferent stimulation elicit a long-term depression (LTD) that is specific to the stimulated input. The induction of LTD was blocked by the extracellular application of okadaic acid or calyculin A, two inhibitors of protein phosphatases 1 and 2A. The loading of CA1 cells with microcystin LR, a membrane-impermeable protein phosphatase inhibitor, or calmodulin antagonists also blocked or attenuated LTD. The application of calyculin A after the induction of LTD reversed the synaptic depression, suggesting that phosphatase activity is required for the maintenance of LTD. These findings indicate that the synaptic activation of protein phosphatases plays an important role in the regulation of synaptic transmission.
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PMID:An essential role for protein phosphatases in hippocampal long-term depression. 839 1


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