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)

Changes in synaptic plasticity are involved in pathophysiology of depression and in the mechanism of antidepressants. Ca(2+)/calmodulin (CaM) kinase II, a protein kinase involved in synaptic plasticity, has been previously shown to be a target of antidepressants. We previously found that antidepressants activate the kinase in hippocampal neuronal cell bodies by increasing phosphorylation at Thr(286), reduce the kinase phosphorylation in synaptic membranes, and in turn its phosphorylation-dependent interaction with syntaxin-1 and the release of glutamate from hippocampal synaptosomes. Here, we investigated the chronic effect of different antidepressants (fluoxetine, desipramine, and reboxetine) on the expression and function of the kinase in distinct subcellular compartments in order to dissect the different kinase pools affected. Acute treatments did not induce any change in the kinase. In total tissue extracts chronic drug treatments induced activation of the kinase; in hippocampus (HC), but not in prefrontal/frontal cortex, this was partially accounted for by increased Thr(286) phosphorylation, suggesting the involvement of different mechanisms of activation. In synaptosomes, all drugs reduced the kinase phosphorylation, particularly in HC where, upon fractionation of the synaptosomal particulate into synaptic vesicles and membranes, we found that the drugs induced a redistribution and differential activation of the kinase between membranes and vesicles. Furthermore, a large decrease in the level and phosphorylation of synapsin I located at synaptic membranes was consistent with the observed decrease of CaM kinase II. Overall, antidepressants induce a complex pattern of modifications in distinct subcellular compartments; at presynaptic level, these changes are in line with a dampening of glutamate release.
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PMID:Chronic antidepressants induce redistribution and differential activation of alphaCaM kinase II between presynaptic compartments. 1735 71

There is growing concern about long-term neurodevelopmental outcomes after neonatal corticosteroid treatment for chronic lung disease (CLD). Here, we use a protocol with tapering doses of dexamethasone (DEX) or hydrocortisone (HC) proportional to those used in preterm infants to examine the long-term consequences of these treatments on hippocampal synaptic plasticity and associative memory in later life. We found that neonatal DEX, but not HC, treatment impairs long-term potentiation (LTP) but enhances long-term depression (LTD) induction in adolescent rats. The effects of neonatal DEX treatment on LTP and LTD were prevented when the animals were given glucocorticoid receptor antagonist, RU38486, before DEX administration. We also found that neonatal DEX, but not HC, treatment induces a profound increase in the autophosphorylation of a isoform of Ca2+/calmodulin-dependent protein kinase II at threonine-286 and a decrease in the protein phosphatase 1 expression. In addition, only neonatal DEX treatment disrupts memory retention in rats subjected to passive avoidance learning tasks. These results demonstrate that only neonatal DEX treatment alters the hippocampal synaptic plasticity and associative memory formation in later life and thus suggest that HC may be a safer alternative to DEX for the treatment of CLD in the neonatal period.
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PMID:Effects of neonatal corticosteroid treatment on hippocampal synaptic function. 1762 55

Phosphorylation-dependent changes in AMPA receptor function have a crucial role in activity-dependent forms of synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD). Although three previously identified phosphorylation sites in AMPA receptor glutamate receptor 1 (GluR1) subunits (S818, S831, and S845) appear to have important roles in LTP and LTD, little is known about the role of other putative phosphorylation sites in GluR1. Here, we describe the characterization of a recently identified phosphorylation site in GluR1 at threonine 840. The results of in vivo and in vitro phosphorylation assays suggest that T840 is not a substrate for protein kinases known to phosphorylate GluR1 at previously identified phosphorylation sites, such as protein kinase A, protein kinase C, and calcium/calmodulin-dependent kinase II. Instead, in vitro phosphorylation assays suggest that T840 is a substrate for p70S6 kinase. Although LTP-inducing patterns of synaptic stimulation had no effect on GluR1 phosphorylation at T840 in the hippocampal CA1 region, bath application of NMDA induced a strong, protein phosphatase 1- and/or 2A-mediated decrease in T840 phosphorylation. Moreover, GluR1 phosphorylation at T840 was transiently decreased by a chemical LTD induction protocol that induced a short-term depression of synaptic strength and persistently decreased by a chemical LTD induction protocol that induced a lasting depression of synaptic transmission. Together, our results show that GluR1 phosphorylation at T840 is regulated by NMDA receptor activation and suggest that decreases in GluR1 phosphorylation at T840 may have a role in LTD.
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PMID:NMDA receptor activation dephosphorylates AMPA receptor glutamate receptor 1 subunits at threonine 840. 1804 15

Mitogen-activated protein kinases (MAPKs) are serine/threonine kinases that play an instrumental role in signal transduction from the cell surface to the nucleus. These enzymes are major intracellular mediators of developmental events and recently have been shown to control also synaptic plasticity processes [Sweatt, J.D., 2004. Mitogen-activated protein kinases in synaptic plasticity and memory. Curr. Opin. Neurobiol. 14, 311-317; Thomas, G.M., Huganir, R.L., 2004. MAPK cascade signalling and synaptic plasticity. Nat. Rev. Neurosci. 5, 173-183]. Mammalian members of this family are extracellular signal-regulated kinases 1/2 (ERK 1/2), c-Jun amino-terminal kinases or stress-activated protein kinases (JNK/SAPKs) and p38 kinases (p38(MAPK)). At the level of the visual system, it has been demonstrated that the ERK pathway regulates developmental plastic processes at both retino-thalamic and thalamo-cortical level and that p38(MAPK) controls a peculiar form of long-term depression in the visual cortex [Di Cristo, G., Berardi, N., Cancedda, L., Pizzorusso, T., Putignano, E., Ratto, G.M., Maffei, L., 2001. Requirement of ERK activation for visual cortical plasticity. Science 292, 2337-2340; Naska, S., Cenni, M.C., Menna, E., Maffei, L., 2004. ERK signaling is required for eye-specific retino-geniculate segregation. Development 131, 3559-3570; Xiong, W., Kojic, L.Z., Zhang, L., Prasad, S.S., Douglas, R., Wang, Y., Cynader, M.S., 2006. Anisomycin activates p38 MAP kinase to induce LTD in mouse primary visual cortex. Brain Res. 1085, 68-76]. Here, as a first approach to gain more insight on the role of two MAPKs - ERK1/2 and p38(MAPK) - in visual system maturation, we characterized by western blot the regulation of their phosphorylation/activation in rat retina, superior colliculus and visual cortex, during postnatal development from birth to adult age. Our main results show that: (i) in the retina p38(MAPK) activation peaks at P4, and then, from P15 to P45, both ERK1/2 and p38(MAPK) phosphorylation increases; (ii) in the superior colliculus phosphorylation of both MAPKs increases between P4 and P15; (iii) in the visual cortex ERK1/2 phosphorylation increases from P15 to P45, while phosphorylation of p38(MAPK) increases starting from P4. The present data demonstrate a distinct regulation of the activation of ERK1/2 and p38(MAPK) in the three visual areas analyzed which occurs in temporal correlation with critical events for visual system maturation. These results suggest an important role for ERK1/2 and p38(MAPK) in the postnatal development of the rat visual system.
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PMID:The activation of ERK1/2 and p38 mitogen-activated protein kinases is dynamically regulated in the developing rat visual system. 1828 Jun 91

Arousal and maintenance of a wake state is dependent on the hypothalamic hypocretin/orexin system. We found that hypocretin neurons are depressed by opiates, drugs of abuse that reduce cognitive alertness. Met-enkephalin (mENK), an endogenous opioid, and exogenous opiates such as morphine inhibited the hypocretin system by direct actions on the cell body that include reduced spike frequency, hyperpolarization, increased G-protein-coupled inwardly rectifying K(+) channel current, and attenuated calcium current, and indirectly through reducing excitatory synaptic tone by a presynaptic mechanism. CTAP (H-d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH(2)) and naloxone, antagonists of mu-opioid receptors, blocked mu agonist actions. In the absence of exogenous opioids, mu receptor antagonists enhanced activity of the hypocretin system, suggesting ongoing inhibition by endogenous receptors. Morphine pretreatment attenuated subsequent excitatory responses to hypocretin, suggesting a long-lasting depression caused by opiate exposure. Chronic exposure to morphine reduced subsequent responses to morphine and to mENK, but increased the response to opioid receptor antagonists. Together, these data are consistent with the view that the hypocretin system may be an important direct target for drugs of abuse, including opiates, that induce sedation and mental lethargy.
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PMID:Mu-opioid receptor-mediated depression of the hypothalamic hypocretin/orexin arousal system. 1833 11

Protein phosphorylation is a major mechanism for the regulation of synaptic transmission. Previous studies have shown that several serine/threonine kinases are involved in the induction of long-term depression (LTD) at excitatory synapses on a Purkinje neuron (PN) in the cerebellum. Here, we show that Src-family protein tyrosine kinases (SFKs) are involved in the regulation of the LTD induction. Intracellular application of c-Src suppressed LTD. We also show that application of a SFK-selective inhibitor PP2 recovered LTD from the suppression caused by the inhibition of mGluR1 activity. These results indicate that SFKs negatively regulate the LTD induction at excitatory synapses on a cerebellar PN.
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PMID:Src-family protein tyrosine kinase negatively regulates cerebellar long-term depression. 1845 55

A synthetic derivative of the endogenous peptide tuftsin heptapeptide selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro) possesses an anxiolytic and psychostimulant effect, and represents a working element of a new peptide drug having completed the third phase of the clinical testing as a selective anxiolytic. The neurobiochemical spectrum of selank action combines mechanisms which are characteristics of antidepressants and psychostimulants: activation of the brain monoaminergic systems, dopamine synthesis and turnover, and modulation of the tyrosine hydroxylase activity. The aim of this study was to investigate the effect of selank in a new model of inherited (genetically-based) symptoms of depression in behavior of inbred WAG/Rij rats in comparison with its effect on situation-provoked symptoms of depression in behavior of BALB/c mice. Outbred Wistar rats constituted control group. Selank in high doses (1000-2000 microg/kg), after repeated injection counteracted symptoms of depression in behavior of WAG/Rij rats (increased immobilization in the forced swimming test and decreased sucrose intake or preference (anhedonia)). Selank in low doses (100 and 300 microg/kg) after single injection reduced the duration of immobility of BALB/c mice in the forced swimming test, but did not exert significant effect after repeated injection or after injection in high doses (600 and 900 microg/kg). Selank did not affect the level of general locomotor activity and anxiety in WAG/Rij rats, and did not exert substantial effect on the behavior of control Wistar rats. The results demonstrate the presence of antidepressant component in the spectrum of neuropsychotrophyc activity of selank and indicate the higher reliability of a new experimental model of depression (the WAG/Rij rats) as compared to the standard forced swimming test for the determination of antidepressant activity of a pharmacological drug.
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PMID:[Effects of heptapeptide selank on genetically-based and situation-provoked symptoms of depression in behavior in WAG/Rij and Wistar rats, and in BALB/c mice]. 1866 85

To test the hypothesis that ammonia detoxification in ruminants consumes amino acids to the detriment of milk protein production, we infused four lactating dairy cows with ammonium acetate or sodium acetate in switchback experiments. Plasma ammonia concentrations increased to 411 microm within 1 h of the start of infusion of ammonium acetate at 567 mmol/h. The rate constant for ammonia clearance from plasma was 0 x 054/min and the half-life was 12 x 9 min. Infusion at 567 mmol/h for 1 h followed by 1 h without infusion, repeated four times between am- and pm-milking, caused a decrease in feed intake. Compared with sodium acetate, continuous infusion of ammonium acetate at 360 mmol/h throughout an entire 10-h milking interval increased plasma ammonia concentrations to 193 microm and caused a 20% decrease in milk, protein and lactose production with no effect on percentage composition of milk or the yield of milk fat. Arterial concentrations of glucose and non-esterified fatty acids tended to increase; there was no effect on arterial acetate, beta-hydroxybutyrate or triacylglcerol, and branched-chain amino acids, Lys and Thr decreased. Mammary plasma flow, estimated by assuming 100% uptake/output of Phe+Tyr, was significantly correlated with milk yield. Mammary uptakes of acetate tended to be reduced by hyperammonaemia, but uptakes of other energy metabolites and amino acids were not affected. Thus, while an increase in amino acid consumption during hyperammonaemia was apparent from the drop in circulating concentrations of Leu, Ile, Val, Lys and Thr, there was no evidence to support the hypothesis that milk yield is affected by the lower concentrations. An ammonia-induced depression in feed intake may have caused the decrease in milk synthesis.
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PMID:The effect of short-term hyperammonaemia on milk synthesis in dairy cows. 1892 95

Abnormal protein phosphorylation has been associated with several neurodegenerative disorders, including Alzheimer's disease (AD). Abeta is the toxic peptide that results from proteolytic cleavage of the Alzheimer's amyloid precursor protein, a process where protein phosphatases are known to impact. The data presented here demonstrates that protein phosphatase 1 (PP1), an abundant neuronal serine/threonine-specific phosphatase highly enriched in dendritic spines, is specifically inhibited by Abeta peptides both in vitro and ex vivo. Indeed, the pathologically relevant Abeta(1-40) and Abeta(1-42) peptides, as well as Abeta(25-35), specifically inhibit PP1 with low micromolar potency, as compared to inactive controls and other disease related peptides (e.g. the prion related Pr(118-135) and Pr(106-126)). Interestingly, PP1 inhibition is increased by Abeta aggregation, indicating a possible direct neurotoxic effect of the aggregated peptide. PP1 involvement in processes like long-term depression, memory and learning, and synaptic plasticity, prompt us to suggest that PP1 may constitute an important physiological target for Abeta and, therefore, increased Abeta production and/or aggregation may lead to abnormal PP1 activity and likely contribute to the progressive neuropsychiatric AD condition. Thus, PP1 activity and levels constitute potential biomolecular candidates for diagnostics and therapeutics.
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PMID:PP1 inhibition by Abeta peptide as a potential pathological mechanism in Alzheimer's disease. 1902 67

The serotonin transporter (SERT) regulates extracellular levels of serotonin (5-hydroxytryptamine, 5HT) in the brain by transporting 5HT into neurons and glial cells. The human SERT (hSERT) is the primary target for drugs used in the treatment of emotional disorders, including depression. hSERT belongs to the solute carrier 6 family that includes a bacterial leucine transporter (LeuT), for which a high resolution crystal structure has become available. LeuT has proved to be an excellent model for human transporters and has advanced the understanding of solute carrier 6 transporter structure-function relationships. However, the precise structural mechanism by which antidepressants inhibit hSERT and the location of their binding pockets are still elusive. We have identified a residue (Ser-438) located within the 5HT-binding pocket in hSERT to be a critical determinant for the potency of several antidepressants, including the selective serotonin reuptake inhibitor citalopram and the tricyclic antidepressants imipramine, clomipramine, and amitriptyline. A conservative mutation of Ser-438 to threonine (S438T) selectively increased the K(i) values for these antidepressants up to 175-fold. The effects of introducing a protein methyl group into the 5HT-binding pocket by S438T were absent or reduced for analogs of these antidepressants lacking a single methyl group. This suggests that these antidepressants interact directly with Ser-438 during binding to hSERT, implying an overlapping localization of substrate- and inhibitor-binding sites in hSERT suggesting that antidepressants function by a mechanism that involves direct occlusion of the 5HT-binding site.
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PMID:Location of the antidepressant binding site in the serotonin transporter: importance of Ser-438 in recognition of citalopram and tricyclic antidepressants. 1921 30


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