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)

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

It has been proposed that the long-term depression (LTD) seen following low frequency stimulation (LFS) in the rat hippocampus involves calcineurin. We have tested this by examining the effect of FK506, a macrolide which blocks calcineurin at nanomolar concentrations, on synaptic transmission in the rat hippocampal slice at a concentration of 1 microM which has been shown to block LTD in the visual cortex. The effect of FK506 on long-term potentiation (LTP) and spontaneous transmitter release was also studied. The magnitude of LTD induced by LFS was 16.7 +/- 2.4% in control which was not significantly different from the 22.3 +/- 3.0% seen in the same preparations after exposure to FK506 for 25-30 min. In contrast the magnitude of LTD induced 'de novo' in preparations exposed to FK506 was significantly reduced. FK506 had no significant effect on LTP, miniature EPSP frequency, miniature EPSP amplitude, resting membrane potential or input resistance. These results, therefore, support the hypothesis that calcineurin is involved in 'de novo' LTD but it appears that an event is triggered by LFS whereby FK506-insensitive LTD can subsequently be activated by a second episode of LFS.
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PMID:Only 'de novo' long-term depression (LTD) in the rat hippocampus in vitro is blocked by the same low concentration of FK506 that blocks LTD in the visual cortex. 882 55

It has been shown that okadaic acid (OA) diminishes insulin secretion of rat pancreatic islets in response to glucose, glyceraldehyde and KCl. Glucose, glyceraldehyde and KCl cause release of insulin by depolarization and subsequent opening of L-type calcium channels. Calcium entry into cells is thought to be related to protein phosphorylation. To evaluate whether or not OA mediated inhibition of insulin secretion in response to depolarization might be due to an interference with calcium uptake, we studied its effect on KCl (30 mM)-induced increases of cytosolic calcium and discharge of insulin in the insulin secreting clonal tumor cell line RINm5F. OA inhibited KCl-stimulated insulin release in concentrations > or = 1 microM. In intact RINm5F cells similar concentrations of OA decreased the activity of protein phosphates PP-1/PP-2A and inhibited the depolarization-induced rise of cytosolic calcium ([Ca2+]i). The latter action could also be achieved with the protein phosphatase inhibitor calyculin A, whereas the OA analogue 1-nor-okadaone, which is without effect on phosphatases, did not affect [Ca2+]i or insulin release. It is concluded that depression of depolarization-induced insulin secretion by OA is due to inhibition of calcium entry along voltage dependent calcium channels. The data also suggest that in RINm5F cells protein phosphatases PP-1/PP-2A are related to the function of voltage-dependent calcium channels.
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PMID:The phosphatase inhibitor okadaic acid blocks KCl-depolarization-induced rise of cytosolic calcium of rat insulinoma cells (RINm5F). 885 85

A rise in Ca2+ concentration at postsynaptic sites provides an initial step in inducing both the long-term potentiation (LTP) and long-term depression (LTD) in the CA1 region of the hippocampus. LTP induction requires the activation of Ca(2+)-sensitive protein kinases following the rise in Ca2+. By contrast, the activity of protein phosphatase(s) appears to be critical to induce LTD. Here we demonstrate that inhibition of the synthesis of calcineurin A alpha and A beta, catalytic subunits of Ca2+/calmodulin- (CaM) dependent protein phosphatase, reduces the threshold of induction for commissural-CA1 LTP in anesthetized rats. In rats administered antisense oligodeoxynucleotides (ODNs) against calcineurin A alpha and A beta intraventricularly for 7 days, a brief tetanic stimulation to the CA3 region, which in the control case was below threshold for the induction of LTP, now produced a long-lasting increase in both the EPSP slope and the amplitude of population spike recorded from the commissural-CA1 pathway. Western blot analysis of calcineurin showed that the threshold reduction was accompanied by a selective decrease in the protein levels in the hippocampus. Thus our study provides direct evidence that calcineurin per se has an antagonizing role in LTP induction. Complementary experiments with the selective calcineurin inhibitor, FK506, also showed the reduction of LTP threshold in a dose-dependent manner. These results, together with previous studies, support the hypothesis that the quantitative phosphorylation level of critical intracellular proteins determines whether the synaptic efficacy will increase or decrease after the activity-dependent rise in postsynaptic Ca2+.
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PMID:A facilitatory effect on the induction of long-term potentiation in vivo by chronic administration of antisense oligodeoxynucleotides against catalytic subunits of calcineurin. 888 51

Long-term potentiation (LTP) and long-term depression (LTD) are calcium-dependent forms of synaptic plasticity observed in area CA1 of the hippocampus. Low-frequency tetani (1-5 Hz) activates protein phosphatases to induce LTD, whereas high-frequency tetani (> 25 Hz) activates protein kinases to induce LTP. A tetanus at an intermediate frequency (10 Hz), however, does not result in a change in synaptic efficacy [Dudek and Bear, (1992), Proc. Natl. Acad. Sci. USA, 89:4363-4367]. We hypothesized that the 10-Hz tetanus results in no long-term change in synaptic efficacy due to a balance of the activity of protein phosphatases and protein kinases. We manipulated protein kinase/phosphatase activity at a 10-Hz tetanus to test this hypothesis. A 10-Hz tetanus under normal conditions results in a transient depression which returns to baseline in 25 min. However, inhibiting kinase activity with the protein kinase inhibitor H-7, or decreasing extracellular calcium concentration, results in the 10-Hz tetanus, inducing LTD. Conversely, inhibiting phosphatase activity with the protein phosphatase inhibitor tautomycin, or increasing extracellular calcium concentration, results in the 10-Hz tetanus, inducing LTP. These results suggest that the relative balance of protein kinase and phosphatase activity (and/or the calcium levels activating them) determines the expression of specific forms of synaptic plasticity, and that these forms lie on a continuum.
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PMID:Protein kinase and phosphatase activity regulate the form of synaptic plasticity expressed. 889 Apr 51

Calcineurin is a serine/threonine protein phosphatase 2B widely distributed in the brain. However, its role in brain function remains unknown. Recent data indicate that calcineurin can participate in long-term depression or long-term potentiation in rat hippocampus. Obviously, calcineurin can also be involved in numerous brain diseases, such as ischaemic hippocampal damage when the protein dephosphorylation system is markedly altered and hyperphosphorylation of the microtubule system in Alzheimer's disease. Besides, abnormal phosphorylation of the cytoskeletal proteins affecting the synaptic signalling can lead to different pathological disorders in the brain. In this study we analysed in more detail the localization of calcineurin in neuronal elements by using confocal microscopy and immunocytochemical approaches to record the enzyme expression in cultured rat dorsal root ganglion neurons. This is the first report showing that calcineurin immunoreactivity is highly expressed in dorsal root ganglion neurons and it is localized mainly near the inner surface of the plasma membrane. Immunostaining of these cells by anti-beta subunits of voltage-operated Ca2+ channels showed that distribution of calcium channel beta-subunit and calcineurin is very similar. Our findings confirm that the function of calcineurin can be directly connected with the activity of voltage-operated calcium channels.
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PMID:Evidence for colocalization of calcineurin and calcium channels in dorsal root ganglion neurons. 915 45

Two distinct forms of long-term depression (LTD), one dependent on the activation of NMDA receptors (NMDARs) and the other dependent on the activation of metabotropic glutamate receptors (mGluRs), are shown to coexist in CA1 hippocampal pyramidal cells of juvenile (11-35 day-old) rats. Both forms were pathway specific and required membrane depolarization and a rise in postsynaptic Ca2+. mGluR-LTD, but not NMDAR-LTD, required the activation of T-type Ca2+ channels, group 1 mGluRs, and protein kinase C, while NMDAR-LTD, but not mGluR-LTD, required protein phosphatase activity. NMDAR-LTD was associated with a decrease in the size of quantal excitatory postsynaptic currents, whereas for mGluR-LTD there was no change in quantal size, but a large decrease in the frequency of events. NMDAR-LTD, but not mGluR-LTD, reversed NMDAR-dependent long-term potentiation, and NMDAR-LTD was unaffected by prior saturation of mGluR-LTD. These findings indicate that NMDAR-LTD and mGluR-LTD are mechanistically distinct forms of synaptic plasticity.
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PMID:Two distinct forms of long-term depression coexist in CA1 hippocampal pyramidal cells. 920 64

The neural substrates of learning and memory most likely involve activity-dependent long-term changes in synaptic strength, including long-term potentiation and long-term depression. A critical element in the cascade of events hypothesized to underlie such changes in synaptic function is modification of protein phosphorylation. Long-term depression is thought to involve decreases in protein phosphorylation, which could result from reduction in protein kinase activity and/or enhancement in protein phosphatase activity. We present here direct evidence that long-term depression in the hippocampus in vivo is associated with an increase in the activity of the serine/threonine phosphatases 1 and 2A. The increase in activity of phosphatase 1 was transient, whereas that of phosphatase 2A lasted > 65 min after the induction of long-term depression. Blockade of long-term depression prevented the observed increases in phosphatase activity, as did selective inhibition of phosphatase 1 and 2A. Induction of long-term depression had no effect on the level of either phosphatase, which suggests that our results reflect increases in the intrinsic activity of these two enzymes. Our findings are consistent with a model of synaptic plasticity that implicates protein dephosphorylation by serine/threonine phosphatases in the early maintenance and/or expression of long-term depression of synaptic strength.
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PMID:Transient and persistent increases in protein phosphatase activity during long-term depression in the adult hippocampus in vivo. 969 9

We have found that two distinct forms of long-term depression (LTD), one dependent on the activation of NMDA receptors (NMDARs) and the other dependent on the activation of metabotropic glutamate receptors (mGluRs), coexist in pyramidal cells of the CA1 region of the hippocampus of juvenile rats (11-35 days). Both forms were pathway specific, required membrane depolarization, and were blocked by chelating postsynaptic Ca2+ with BAPTA. The mGluR-LTD, but not the NMDAR-LTD, was blocked by the T-type Ca2+ channel blocker Ni2+ and intracellular administration of a protein kinase C inhibitory peptide. In contrast, the protein phosphatase inhibitor Microcystin LR blocked NMDAR-LTD, but not mGluR-LTD. NMDAR-LTD is associated with a decrease in the size of quantal excitatory postsynaptic currents, whereas for mGluR-LTD there was no change in quantal size, but a large decrease in the frequency of events. While mGluR-LTD did not interact with NMDAR-dependent long term potentiation (LTP), NMDAR-LTD was capable of reversing LTP. Prior saturation of mGluR-LTD had no effect on NMDAR-LTD. NMDAR-LTD and mGluR-LTD thus appear to be mechanistically distinct forms of synaptic plasticity in that they share neither induction nor expression mechanisms.
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PMID:NMDA receptor-dependent and metabotropic glutamate receptor-dependent forms of long-term depression coexist in CA1 hippocampal pyramidal cells. 975 87


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