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)

Saturation binding of [3H]cAMP to the regulatory subunit of cAMP-dependent protein kinase (PKA) was measured in the soluble fraction of brain samples, obtained at post-mortem, from suicides with a firm retrospective diagnosis of depression and individually matched controls. Suicides were subdivided into those who had been free of antidepressant drugs for at least 3 months and those in whom prescription of antidepressants was clearly documented. In antidepressant-free suicides, we found no significant differences in the number or affinity of [3H]cAMP binding sites in the five regions studied. In antidepressant-treated suicides however, Bmax values were lower in all regions, reaching statistical significance in parietal cortex and amygdala. Kd values for antidepressant-treated suicides were significantly higher in parietal cortex, temporal cortex and amygdala. These results suggest the regulatory subunit of PKA is unaltered in depression, but is influenced by antidepressant drugs.
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PMID:Brain [3H]cAMP binding sites are unaltered in depressed suicides, but decreased by antidepressants. 920 52

The nucleus accumbens is a forebrain region that mediates cocaine self-administration and withdrawal effects in animal models of cocaine dependence. Considerable evidence suggests an important role of dopamine D1 receptors in these effects. Using a combination of current-clamp recordings in brain slices and whole-cell patch-clamp recordings from freshly dissociated neurons, we found that nucleus accumbens neurons are less excitable in cocaine withdrawn rats because of a novel form of plasticity: reduced whole-cell sodium currents. Three days after discontinuation of repeated cocaine injections, nucleus accumbens neurons recorded in brain slices were less responsive to depolarizing current injections, had higher action potential thresholds, and had lower spike amplitudes. Freshly dissociated nucleus accumbens neurons from cocaine-pretreated rats exhibited diminished sodium current density and a depolarizing shift in the voltage-dependence of sodium channel activation. These effects appear to be related to enhanced basal phosphorylation of sodium channels because of increased transmission through the dopamine D1 receptor/cAMP-dependent protein kinase pathway. The effects of repeated cocaine administration were not mimicked by repeated injections of the local anesthetic lidocaine and were not observed in neurons within the motor cortex, indicating that they did not result from local anesthetic actions of cocaine. Because nucleus accumbens neurons are normally recruited to coordinate response patterns of movement and affect, the decreased excitability during cocaine withdrawal may be related to symptoms such as anergia, anhedonia, and depression.
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PMID:Whole-cell plasticity in cocaine withdrawal: reduced sodium currents in nucleus accumbens neurons. 1197 3

Nootropic agents are proposed to serve as cognition enhancers. The underlying mechanism, however, is largely unknown. The present study was conducted to assess the intracellular signal transduction pathways mediated by the nootropic nefiracetam in the native and mutant Torpedo californica nicotinic acetylcholine (ACh) receptors expressed in Xenopus laevis oocytes. Nefiracetam induced a short-term depression of ACh-evoked currents at submicromolar concentrations (0.01-0.1 microM) and a long-term enhancement of the currents at micromolar concentrations (1-10 microM). The depression was caused by activation of pertussis toxin-sensitive, G protein-regulated, cAMP-dependent protein kinase (PKA) with subsequent phosphorylation of the ACh receptors; in contrast, the enhancement was caused by activation of Ca(2+)-dependent protein kinase C (PKC) and the ensuing PKC phosphorylation of the receptors. Therefore, nefiracetam interacts with PKA and PKC pathways, which may explain a cellular mechanism for the action of cognition-enhancing agents.
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PMID:Nefiracetam modulates acetylcholine receptor currents via two different signal transduction pathways. 944 26

Although the cholinergic system is proposed to be involved in methamphetamine (MeAMPH)-induced abnormal behaviors, no direct evidence has been provided yet. The present study investigated the effects of MeAMPH on acetylcholine (ACh)-evoked currents in the neuronal nicotinic ACh receptors (alpha7) expressed in Xenopus oocytes. MeAMPH enhanced the currents in a time- and dose-dependent manner at concentrations ranged from 1 nM to 3 microM, reaching a maximum of 150% 30 min after treatment. Lesser potentiation was observed at higher concentrations (>3 microM) and instead, the currents were inhibited at more than 10 microM MeAMPH with a slow reverse after washing-out of the drug. The current potentiation or depression was caused via a pathway independent of G-protein, protein kinase C or cAMP-dependent protein kinase. The ACh dose-response curve was shifted to the left and to the right after treatment with 1 and 100 microM MeAMPH, respectively, suggesting that MeAMPH potentiated or inhibited ACh-evoked currents by a change in the affinity for ACh. The actions of MeAMPH on the neuronal nicotinic ACh receptors may represent a cellular mechanism for MeAMPH-induced abnormal behaviors and sensitization.
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PMID:Methamphetamine modulates ACh-evoked currents in Xenopus occytes expressing the rat alpha7 receptors. 946 59

Nitric oxide (NO) is thought to play an essential role in neuronal processing, but the downstream mechanisms of its action remain unclear. We report here that NO analogs reduce GABA-gated currents in cultured retinal amacrine cells via two distinct, but convergent, cGMP-dependent pathways. Either extracellular application of the NO-mimetic S-nitroso-N-acetyl-penicillamine (SNAP) or intracellular perfusion with cGMP depressed GABA currents. This depression was partially blocked by a pseudosubstrate peptide inhibitor of cGMP-dependent protein kinase (PKG), suggesting both PKG-dependent and independent actions of cGMP. cAMP-dependent protein kinase (PKA) is known to enhance retinal GABA responses. 8-Bromoinosine 3',5'-cyclic monophosphate (8Br-cIMP), which activates a type of cGMP-stimulated phosphodiesterase that hydrolyzes cAMP, also significantly reduced GABA currents. 1-Methyl-3-isobutylxanthine (IBMX), a nonspecific phosphodiesterase (PDE) inhibitor, blocked both the action of 8Br-cIMP and the portion of SNAP-induced depression that was not blocked by PKG inhibition. Our results suggest that NO depresses retinal GABAA receptor function by simultaneously upregulating PKG and downregulating PKA.
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PMID:Nitric oxide depresses GABAA receptor function via coactivation of cGMP-dependent kinase and phosphodiesterase. 950 95

The phosphorylation state of phosphofructokinase from the mantle tissue of the facultative anaerobe mollusk Mytilus galloprovincialis was determined by a back-phosphorylation technique. The incubation of intact mantle tissue with 8-bromoadenosine 3':5'-cyclic monophosphate increased significantly the phosphate content of phosphofructokinase, which indicates that the enzyme can be phosphorylated in vivo by endogenous cAMP-dependent protein kinase. The phosphate content of mussel phosphofructokinase changes significantly during the year, in agreement with the kinetic data that show a more active enzyme form in earlier autumn. These results suggest that cAMP-dependent phosphorylation of phosphofructokinase can be partially responsible for the observed glycolytic changes associated with the annual gametogenic cycle that takes place in the mantle tissue of the mollusk. On the contrary, no differences were observed between aerobic and 24-h hypoxic mussels with regard to the phosphorylation state and the kinetic constants of phosphofructokinase. This result is inconsistent with the hypothesis that phosphorylation of phosphofructokinase is involved in the glycolytic depression that takes place during the long-term environmental hypoxia that the mollusk can undergo.
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PMID:In vivo phosphorylation of phosphofructokinase from the bivalve mollusk Mytilus galloprovincialis. 960 59

Nitric Oxide (NO) is released from parallel fibers (PFs) after PF stimulation. NO-cGMP signaling is essential for long-term depression (LTD) in cerebellar PF-Purkinje cell synapses, which also exhibit presynaptic long-term potentiation (LTP) after tetanic PF stimulation. This LTP is dependent on cAMP but not NO-cGMP signaling. In this study, we analyzed long-term changes of NO release from PFs in rat cerebellar slices using electrochemical NO probes. Repetitive PF stimulation at 10 Hz for 2 sec elicited a transient increase in NO concentration (2.2 +/- 0.1 nM; mean +/- SEM; n = 116). This NO release exhibited long-term potentiation (LTPNO) by 36 +/- 3% (n = 15) after tetanic PF stimulation. Induction of LTPNO was not affected by Glu receptor antagonists. NO release from PFs was also potentiated by L-Arg (ARG) (100 microM), forskolin (50 microM), and 8-bromo-cAMP (Br-cAMP) (1 mM) but not by 1,9-dideoxyforskolin (50 microM), a biologically inactive analog of forskolin. The potentiation induced by forskolin was significantly suppressed by H89 (10 microM), a blocker of cAMP-dependent protein kinase. The potentiation induced by forskolin, but not that induced by Arg, interfered with LTPNO. H89 (10 microM) and KT5720 (1 microM), another blocker of cAMP-dependent protein kinase, but not KT5823 (300 nM), a blocker of cGMP-dependent protein kinase, significantly suppressed LTPNO. These data indicate that neural NO release is under activity-dependent control, just as synaptic transmitter release is. LTPNO might play a role in cross talk between presynaptic and postsynaptic plasticity by facilitating NO-cGMP-dependent postsynaptic LTD after induction of cAMP-dependent presynaptic LTP and LTPNO.
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PMID:cAMP-dependent long-term potentiation of nitric oxide release from cerebellar parallel fibers in rats. 978 63

1. The effects of increase in intracellular adenosine 3':5'-cyclic monophosphate (cAMP) on endothelin-1 (ET-1)-induced generation of inositol phosphates (IPs) and increase in intracellular Ca2+ ([Ca2+]i) were investigated in canine cultured tracheal smooth muscle cells (TSMCs). 2. Pretreatment of TSMCs with either cholera toxin (CTX; 10 microg ml(-1), 4 h), forskolin (10 microM, 30 min), or dibutyryl cAMP (1 mM, 30 min) inhibited ET-1-stimulated Ca2+ mobilization (by 23 +/- 5%, n = 8) and IPs accumulation (by 32 +/- 6%, n = 4). While after treatment with forskolin for 24 h, the cells retained the ability to respond to ET-1-induced Ca2+ mobilization to the same extent as the control group. 3. Forskolin (1-100 microM) inhibited the ET-1-induced increase in [Ca2+]i, but the lower concentrations had little effect on this response. The inhibitory effects of these agents produced both depression of the maximal response and a shift to the right of the concentration-response curve of ET-1 without changing the -logEC50 values. 4. The water-soluble forskolin analogue L-858051, 7-deacetyl-7beta-(gamma-N-methylpiperazino)-butyryl forskolin, significantly inhibited ET-1-stimulated IPs accumulation. In contrast, the addition of 1,9-dideoxy forskolin, an inactive analogue of forskolin, had little effect on stimulated responses. Moreover, SQ-22536, 9-(tetrahydro-2-furanyl)-9H-purin-6-amine, an inhibitor of adenylate cyclase, and both H-89, N-(2-aminoethyl)-5-isoquinolinesulfonamide, and HA-1004, N-(2-guanidinoethyl)-5-isoquinolinesulfonamide, inhibitors of cAMP-dependent protein kinase (PKA), attenuated the ability of forskolin to inhibit ET-1-induced IPs accumulation. These results suggest that activation of cAMP/PKA was involved in these inhibitory effects of forskolin. 5. The locus of this inhibition of forskolin treatment on AlF4(-)-stimulated IPs accumulation was investigated in canine TSMCs. The AlF4(-)-induced IPs accumulation was inhibited by forskolin, supporting that G protein(s) are directly activated by AlF4- and uncoupled to phospholipase C by forskolin treatment. 6. We conclude that cAMP elevating agents inhibit ET-1-stimulated generation of IPs and Ca2+ mobilization in canine cultured TSMCs. Since generation of IPs and increases in [Ca2+]i are very early events in the activation of ET-1 receptors, attenuation of these events by cAMP elevating agents might well contribute to the inhibitory effect of cAMP on tracheal smooth muscle function.
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PMID:Effect of forskolin on endothelin-induced phosphoinositide hydrolysis and calcium mobilization in cultured canine tracheal smooth muscle cells. 978 91

Mossy fiber synapses on hippocampal CA3 pyramidal cells, in addition to expressing an NMDA receptor-independent form of long-term potentiation (LTP), have recently been shown to express a novel presynaptic form of long-term depression (LTD). We have studied the mechanisms underlying mossy fiber LTD and present evidence that it is triggered, at least in part, by a metabotropic glutamate receptor-mediated decrease in adenylyl cyclase activity, which leads to a decrease in the activity of the cAMP-dependent protein kinase (PKA) and a reversal of the presynaptic processes responsible for mossy fiber LTP. The bidirectional control of synaptic strength at mossy fiber synapses by activity therefore appears to be due to modulation of the cAMP-PKA signaling pathway in mossy fiber boutons.
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PMID:A role for cAMP in long-term depression at hippocampal mossy fiber synapses. 980 69

Brief bath application of N-methyl-D-aspartate (NMDA) to hippocampal slices produces long-term synaptic depression (LTD) in CA1 that is (1) sensitive to postnatal age, (2) saturable, (3) induced postsynaptically, (4) reversible, and (5) not associated with a change in paired pulse facilitation. Chemically induced LTD (Chem-LTD) and homosynaptic LTD are mutually occluding, suggesting a common expression mechanism. Using phosphorylation site-specific antibodies, we found that induction of chem-LTD produces a persistent dephosphorylation of the GluR1 subunit of AMPA receptors at serine 845, a cAMP-dependent protein kinase (PKA) substrate, but not at serine 831, a substrate of protein kinase C (PKC) and calcium/calmodulin-dependent protein kinase II (CaMKII). These results suggest that dephosphorylation of AMPA receptors is an expression mechanism for LTD and indicate an unexpected role of PKA in the postsynaptic modulation of excitatory synaptic transmission.
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PMID:NMDA induces long-term synaptic depression and dephosphorylation of the GluR1 subunit of AMPA receptors in hippocampus. 985 70


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