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)

Neuronal plasticity can be defined as adaptive changes in structure and function of the nervous system, an obvious example of which is the capacity to remember and learn. Long-term potentiation and long-term depression are the experimental models of memory in the central nervous system (CNS), and have been frequently utilized for the analysis of the molecular mechanisms of memory formation. Extensive studies have demonstrated that various kinases and phosphatases regulate neuronal plasticity by phosphorylating and dephosphorylating proteins essential to the basic processes of adaptive changes in the CNS. These proteins include receptors, ion channels, synaptic vesicle proteins, and nuclear proteins. Multifunctional kinases (cAMP-dependent protein kinase, Ca2+/phospholipid-dependent protein kinase, and Ca2+/calmodulin-dependent protein kinases) and phosphatases (calcineurin, protein phosphatases 1, and 2A) that specifically modulate the phosphorylation status of neuronal-signaling proteins have been shown to be required for neuronal plasticity. In general, kinases are involved in upregulation of the activity of target substrates, and phosphatases downregulate them. Although this rule is applicable in most of the cases studied, there are also a number of exceptions. A variety of regulation mechanisms via phosphorylation and dephosphorylation mediated by multiple kinases and phosphatases are discussed.
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PMID:Regulation of neuronal plasticity in the central nervous system by phosphorylation and dephosphorylation. 988 50

The effects of cocaine on glycine-induced Cl- current (I(GLY)) of single neurons, freshly isolated from the rat hippocampal CA1 area, were studied with conventional whole-cell recording under voltage-clamp conditions. Cocaine depressed I(GLY) in a concentration-dependent manner, with an IC50 of 0.78 mM. Preincubation with 1 mM cocaine alone had no effect on I(GLY), suggesting that resting glycine channels are insensitive to cocaine. The depression of I(GLY) by cocaine was independent of membrane voltage. Internal cell dialysis with 1 mM cocaine failed to modify I(GLY). Because the depression of I(GLY) was noncompetitive, cocaine may act on the glycine receptor-chloride ionophore complex at a site distinct from that to which glycine binds. The cocaine suppression of I(GLY) was unaffected by 1 microM tetrodotoxin and 1 microM strychnine. Blockers of protein kinase C (Chelerythrine), kinase A (N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide HCl, (H-89)) and Ca-calmodulin-dependent kinase (1-[N,O-bis(5-isoquinoline-sulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperaz ine (KN-62)) were also ineffective, which suggests that these phosphorylating mechanisms do not modulate cocaine-induced suppressant action on I(GLY). This extracellular, strychnine-independent depression of I(GLY) may contribute to cocaine-induced seizures.
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PMID:Cocaine decreases the glycine-induced Cl- current of acutely dissociated rat hippocampal neurons. 1008 75

High-frequency stimulation (HFS) of corticostriatal glutamatergic fibers induces long-term depression (LTD) of excitatory synaptic potentials recorded from striatal spiny neurons. This form of LTD can be mimicked by zaprinast, a selective inhibitor of cGMP phosphodiesterases (PDEs). Biochemical analysis shows that most of the striatal cGMP PDE activity is calmodulin-dependent and inhibited by zaprinast. The zaprinast-induced LTD occludes further depression by tetanic stimulation and vice versa. Both forms of synaptic plasticity are blocked by intracellular 1H-[1,2,4]oxadiazolo[4, 3-a]quinoxalin-1-one (ODQ), a selective inhibitor of soluble guanylyl cyclase, indicating that an increased cGMP production in the spiny neuron is a key step. Accordingly, intracellular cGMP, activating protein kinase G (PKG), also induces LTD. Nitric oxide synthase (NOS) inhibitors N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME) and 7-nitroindazole monosodium salt (7-NINA) block LTD induced by either HFS or zaprinast, but not that induced by cGMP. LTD is also induced by the NO donors S-nitroso-N-acetylpenicillamine (SNAP) and hydroxylamine. SNAP-induced LTD occludes further depression by HFS or zaprinast, and it is blocked by intracellular ODQ but not by L-NAME. Intracellular application of PKG inhibitors blocks LTD induced by HFS, zaprinast, and SNAP. Electron microscopy immunocytochemistry shows the presence of NOS-positive terminals of striatal interneurons forming synaptic contacts with dendrites of spiny neurons. These findings represent the first demonstration that the NO/cGMP pathway exerts a feed-forward control on the corticostriatal synaptic plasticity.
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PMID:A critical role of the nitric oxide/cGMP pathway in corticostriatal long-term depression. 1008 63

CaMKII is a calcium-activated kinase that is abundant in neurons and has been strongly implicated in memory and learning. Here we show that low-frequency stimulation of glutamatergic afferents in hippocampal slices from juvenile domestic chicks results in long-term depression of synaptic transmission. This reduction does not require activation of NMDA or metabotropic glutamate receptors and does not require a rise in postsynaptic calcium. However, buffering presynaptic calcium prevents the reduction of the excitatory postsynaptic potential or current that is induced by low-frequency stimulation. In addition, application of the calmodulin antagonist calmidazolium, or the specific CaMKII antagonist KN-93, completely blocks long-term depression. These findings demonstrate a newly discovered form of long-term synaptic depression in the avian hippocampus.
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PMID:Presynaptic long-term depression at a central glutamatergic synapse: a role for CaMKII. 1019 27

Long-term potentiation (LTP) and long-term depression (LTD) are induced presynaptically at the hippocampal mossy fibre-CA3 synapse. Activation of presynaptic metabotropic glutamate receptors (mGluRs) is necessary, but not sufficient for the LTD induction. Using mouse hippocampal slices, we attempted to identify additional presynaptic factors involved in the induction of mossy fibre LTD. Suppression of a rise in the presynaptic intracellular Ca2+ concentration ([Ca2+]i) with a membrane-permeable Ca2+ chelator, 1, 2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetraacetoxymethyl ester (BAPTA-AM), reduced the magnitude of LTD, whereas an increase in Ca2+ influx induced LTD, suggesting that an elevation of presynaptic [Ca2+]i is crucial for the LTD induction. A broad-spectrum protein kinase inhibitor, H-7, blocked LTD without affecting a presynaptic inhibition induced by an mGluR agonist. Furthermore, LTD was reduced by an inhibitor of calmodulin or Ca2+/calmodulin-dependent protein kinases. Thus, we conclude that mossy fibre LTD requires an increase in presynaptic [Ca2+]i and subsequent activation of Ca2+/calmodulin-dependent protein kinases. Because mossy fibre LTP may also require a rise in presynaptic [Ca2+]i, bidirectional long-term plasticity at the mossy fibre synapse is likely to be regulated by presynaptic Ca2+-dependent processes.
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PMID:Calcium-dependent mechanisms involved in presynaptic long-term depression at the hippocampal mossy fibre-CA3 synapse. 1021 16

The phosphorylation of substrate proteins by protein kinases plays a key role in signal transduction and function of neurons. Protein kinases have been associated with several physiological and pathological states including depression. The aim of the present study was to investigate the effect of imipramine and electroconvulsive treatment (ECS), both clinically effective treatments of depression, on the activity of calcium/calmodulin dependent protein kinase II (CaM-KII) in the hippocampus. Our results indicate that repeated (but not acute) imipramine and ECS administration significantly decreased CaM-KII activity by 65 and 70%, respectively, in the soluble fractions from hippocampus. This decreased enzyme activity was accompanied by a proportional decrease (60-70%) of the amount of a-CaM-KII in the same fraction. A single and repeated administration of imipramine produced a significant increase in the activity of CaM-KII (50 and 337%, respectively) in the particulate fraction from hippocampus. Similarly, a single and repeated ECS produced an increase in the enzyme activity by 22 and 240%, respectively. The amount of a-CaM-KII in the particulate fraction was not significantly affected by repeated antidepressant administration. It is postulated that changes in CaM-KII activity following chronic antidepressant treatment might represent and important step in expression of its antidepressive action.
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PMID:The effect of prolonged imipramine and electroconvulsive shock treatment on calcium/calmodulin-dependent protein kinase II in the hippocampus of rat brain. 1022 63

We have shown previously that activation of mGlu receptors using a group I specific mGlu receptor agonist, (R,S)-3,5-dihydroxyphenylglycine (DHPG), can induce long-term depression (LTD) in the CA1 region of the hippocampus (Palmer et al., 1997). We now report that DHPG-induced LTD is facilitated by treatment with KN-62, an inhibitor of certain Ca2+/calmodulin-dependent protein kinases (CaMKs), including CaMKII.
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PMID:A CaMKII inhibitor, KN-62, facilitates DHPG-induced LTD in the CA1 region of the hippocampus. 1022 64

In the central nervous system, release of Ca2+ from intracellular stores contributes to numerous functions, including neurotransmitter release and long-term potentiation and depression. We have investigated the developmental profile and the regulation of inositol 1,4,5-trisphosphate receptor (IP3R) and ryanodine receptor (RyR) in primary cultures of cerebellar granule cells. The expression of both receptor types increases during development. Whereas the expression of type 1 IP3R appears to be regulated by Ca2+ influx through L type channels or N-methyl-D-aspartate (NMDA) receptors, RyR levels increase independently of Ca2+. The main target of Ca2+-influx-regulating IP3R expression is the Ca2+ calmodulin-dependent protein phosphatase calcineurin, because pharmacological blockade of this protein abolishes IP3R expression. Although calcineurin has been shown to regulate the phosphorylation state of the IP3R, the effect described here is at the transcriptional level because IP3R mRNA changes in parallel with protein levels. Thus, calcineurin plays a dual role in IP3R-mediated Ca2+ signaling: it regulates IP3R function by dephosphorylation in the short-term time scale and IP3R expression over more extended periods.
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PMID:Calcineurin controls inositol 1,4,5-trisphosphate type 1 receptor expression in neurons. 1031 64

Down-regulation of cortical beta-adrenoceptors is observed in rodents following chronic treatment with many clinically effective antidepressant therapies. [3H]dihydroalprenolol binding to cortical beta-adrenoceptors was examined in mice treated with the nitric oxide (NO) synthase antagonist N(G)-nitro-L-arginine (L-NNA). Administration of L-NNA (0.1, 0.3 mg/kg) for 21 days produced a significant reduction (28%, 31%, respectively, P<0.05) in [3H]dihydroalprenolol binding to cortical membranes without affecting Kd. Dose 1 mg/kg of L-NNA given chronically also produced a 20% decrease in beta-adrenoceptor density, but this effect was not statistically significant. While chronic treatment with imipramine (15 and 30 mg/kg) produced respectively a 30% and 25% (P<0.05) reduction in the density of [3H]dihydroalpenolol, single injection of either imipramine (15 and 30 mg/kg) or L-NNA (0.1, 0.3, and 1 mg/kg) had no effect on [3H]dihydroalprenolol binding. These findings are consistent with the hypothesis that drugs which can affect the Ca2+ -calmodulin/nitric oxide synthase/guanylyl cyclase signaling pathway may represent a novel approach to the treatment of depression and are congruent with our previous observation, which has demonstrated the antidepressant-like properties of NO synthase inhibitors in the forced swim test.
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PMID:Nitric oxide synthase inhibitors have antidepressant-like properties in mice. 2. Chronic treatment results in downregulation of cortical beta-adrenoceptors. 1039 14

Depression has been treated pharmacologically for over three decades, but the views regarding the mechanism of action of antidepressant drugs have registered recently a major change. It was increasingly appreciated that adaptive changes in postreceptor signaling pathways, rather than primary action of drugs on monoamine transporters, metabolic enzymes, and receptors, are connected to therapeutic effect. For some of the various signaling pathways affected by antidepressant treatment, it was shown that protein phosphorylation, which represents an obligate step for most pathways, is markedly affected by long-term treatment. Changes were reported to be induced in the function of protein kinase C, cyclic AMP-dependent protein kinase, and calcium/calmodulin-dependent protein kinase. For two of these kinases (cyclic AMP- and calcium/calmodulin-dependent), the changes have been studied in isolated neuronal compartments (microtubules and presynaptic terminals). Antidepressant treatment activates the two kinases and increases the endogenous phosphorylation of selected substrates (microtubule-associated protein 2 and synaptotagmin). These modifications may be partly responsible for the changes induced by antidepressants in neurotransmission. The changes in protein phosphorylation induced by long-term antidepressant treatment may contribute to explain the therapeutic action of antidepressants and suggest new strategies of pharmacological intervention.
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PMID:Second messenger-regulated protein kinases in the brain: their functional role and the action of antidepressant drugs. 1061 2


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