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)

Neurogranin (Ng) is a newly discovered brain-specific protein composed of 78 amino acid residues, which mainly located postsynaptically in the cerebral cortex, hippocampus and olfactory bulb in adult human or animals. As a member of calpacitin family, Ng is a protein kinase C (PKC) substrate and calmodulin (CaM) reservoir. In the physiological conditions, Ng forms a complex with CaM, and its CaM-binding affinity was modulated by phosphorylation, oxidation and glutathiolation under the activation of PKC or oxidant stress, which may be involved in the regulation of CaM and CaM-activated proteins, such as CaM-dependent nitric oxide synthase (NOS), CaM-dependent protein kinase II (CaMKII) and CaM-dependent adenylate cyclase (AC). Since most of CaM-activated proteins were involved in long-term potentiation (LTP) and long-term depression (LTD), and the timing pattern of Ng gene expression and protein synthesis are coincidence with synaptogenesis and development, it is suggested that Ng may play an important role in learning, memory and neuroplasticity. In addition, it was found that the changes of Ng expression might associate with certain cerebral pathophysiologic disorders, such as hypothyroidism, sleep-deprivation, brain aging and cerebral hypoxic preconditioning.
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PMID:[Neurogranin: a brain-specific protein]. 1288 41

Cortical map formation requires the accurate targeting, synaptogenesis, elaboration and refinement of thalamocortical afferents. Here we demonstrate the role of Ca2+/calmodulin-activated type-I adenylyl cyclase (AC1) in regulating the strength of thalamocortical synapses through modulation of AMPA receptor (AMPAR) trafficking using barrelless mice, a mutant without AC1 activity or cortical 'barrel' maps. Barrelless synapses are stuck in an immature state that contains few functional AMPARs that are rarely silent (NMDAR-only). Long-term potentiation (LTP) and long-term depression (LTD) at thalamocortical synapses require postsynaptic protein kinase A (PKA) activity and are difficult to induce in barrelless mice, probably due to an inability to properly regulate synaptic AMPAR trafficking. Consistent with this, both the extent of PKA phosphorylation on AMPAR subunit GluR1 and the expression of surface GluR1 are reduced in barrelless neurons. These results suggest that activity-dependent mechanisms operate through an AC1/PKA signaling pathway to target some synapses for consolidation and others for elimination during barrel map formation.
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PMID:Adenylyl cyclase I regulates AMPA receptor trafficking during mouse cortical 'barrel' map development. 1289 88

Second messenger cascades involving G proteins and calcium are known to modulate neurotransmitter release. A prominent effect of such a cascade is the downmodulation of presynaptic calcium influx, which markedly reduces evoked neurotransmitter release. Here we show that G-protein-mediated signalling, such as through GABA (gamma-amino butyric acid) subtype B (GABA(B)) receptors, retards the recruitment of synaptic vesicles during sustained activity and after short-term depression. This retardation occurs through a lowering of cyclic AMP, which blocks the stimulatory effect of increased calcium concentration on vesicle recruitment. In this signalling pathway, cAMP (functioning through the cAMP-dependent guanine nucleotide exchange factor) and calcium/calmodulin cooperate to enhance vesicle priming. The differential modulation of the two forms of synaptic plasticity, presynaptic inhibition and calcium-dependent recovery from synaptic depression, is expected to have interesting consequences for the dynamic behaviour of neural networks.
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PMID:Direct modulation of synaptic vesicle priming by GABA(B) receptor activation at a glutamatergic synapse. 1291 85

Two types of synaptic depression have been described in the hippocampus, long-term depression and depotentiation of long-term potentiation known to recruit the serine/threonine protein phosphatases PP1, PP2A and PP2B (calcineurin). The contribution of each of these protein phosphatases is controversial. To examine the role of the Ca2+/calmodulin-dependent protein phosphatase calcineurin in long-term depression and depotentiation, we analysed the effect of genetically inhibiting calcineurin reversibly in the hippocampus, using the doxycycline-dependent rtTA system in transgenic mice. We show that reducing calcineurin activity has no effect on long-term depression but reversibly affects depotentiation. Consistently, the calcineurin inhibitor FK-506 reproduces the depotentiation impairment observed in the mutant mice but does not affect long-term depression in control animals. In contrast, the PP1/PP2A inhibitor okadaic acid fully blocks both long-term depression and depotentiation. These data demonstrate that the nature of signalling cascades induced by synaptic activity depends on the initial synaptic state. While depression of potentiated synaptic responses requires activation of PP1/PP2A and/or calcineurin, depression of basal synaptic responses depends only on PP1/PP2A activation.
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PMID:Different phosphatase-dependent mechanisms mediate long-term depression and depotentiation of long-term potentiation in mouse hippocampal CA1 area. 1295 26

We developed a microelectroporation method for the transfer of genes into neurons in the cerebral cortex of adult rodents, both rats and mice. We selectively expressed either green-fluorescent protein (GFP) or a Ca2+-binding deficient calmodulin (CaM) mutant in the anterior cingulate cortex (ACC). In mice that expressed GFP, positive neuronal cell bodies were found specifically at the injection site in the ACC. Mice that expressed CaM12, a mutant CaM with two impaired Ca2+ binding sites in the N-terminal lobe, exhibited significant changes in vocalization, locomotion, and sensory functions. Long-term potentiation and long-term depression, two major forms of central plasticity, were completely abolished by expression of CaM12. Mice that expressed CaM34, a mutant CaM with two impaired Ca2+ binding sites in the C-terminal lobe, did not show any significant behavioral or electrophysiological alterations. These findings provide strong evidence that CaM is critical for bidirectional synaptic plasticity. This new method will be useful for investigating gene function in specific brain regions of freely moving animals. Furthermore, this approach also may facilitate gene therapy in adult human brains.
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PMID:Calmodulin regulates synaptic plasticity in the anterior cingulate cortex and behavioral responses: a microelectroporation study in adult rodents. 1296 2

We report evidence that mitochondrially produced superoxide (O(2)(-)) is involved in signaling in hippocampal neurons by examining the relationship between strong but physiological increases in cytosolic free Ca(2+), mitochondrial calcium accumulation, O(2)(-) production, and CREB phosphorylation. Strong depolarization-induced Ca(2+) entry through NMDA or L-type Ca(2+) channels evoked large Ca(2+) transients, a sustained increase in O(2)(-), and a large rise in nuclear CaM and pCREB. Under these conditions, inhibition of mitochondrial Ca(2+) uptake and consequent O(2)(-) production suppressed Ca(2+) entry-induced pCREB elevation, indicating that O(2)(-) produced by mitochondria supports CREB phosphorylation. Similarly, inhibiting mitochondrial respiration blocked O(2)(-) production and also depressed the elevation of pCREB. Blocking calcineurin reversed this depression. We conclude that strong Ca(2+) entry promotes mitochondrial calcium accumulation and the subsequent enhancement of mitochondrial O(2)(-) production, which in turn prolongs the lifetime of pCREB by suppressing calcineurin-dependent pCREB dephosphorylation.
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PMID:Calcium-dependent mitochondrial superoxide modulates nuclear CREB phosphorylation in hippocampal neurons. 1469 72

Although during the last three decades phosphorylation and dephosphorylation systems have been pointed out as the mechanisms used by living cells to control biological processes, it seems that calcium dynamics is the phenomenon that precedes and controls protein activation by the introduction of phosphate groups into distinct protein structures. The process begins with activation of calcium channels that allows the influx of the ion, which once inside the cell leads to calcium-calmodulin complex, a molecule capable of triggering activation of distinct proteinkinases. Thus, the cell in addition to suffering a change in polarity enhances neuroconduction and release of different substances such as hormones and para-hormones, facilitates intra- and intercellular communication, and exerts determinant influence on phenotypic expression by means of promotion of immediate and mediate response genes. Ionic conformational calcium runs short- and long-term facilitation mechanisms, exerting its influence on control of memory through homosynaptic depression and hetersynaptic facilitation processes; triggers autophosphorylation of several enzymes leading and enhancing cellular activity and participates in signal transduction and decodification. Calcium influx rate activates certain groups of phosphatases capable of inhibiting autophosphorylation processes, only as a negative feedback mechanism. In addition, ionic calcium also participates in the "cross-activate" mechanism of proteinkinases A and G, influencing to production of systemic and central nervous system nitric oxide. On these bases, it is possible to guess that future pharmacologic interventions on calcium fluxes could be of invaluable importance in prevention and control of a number of distinct physiopathologic events.
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PMID:[Calcium, the atom triggering life and cellular function]. 1517 33

We report here evidence for endogenous NO signalling in long-term (>1 h) synaptic depression at the neuromuscular junction induced by 20 min of 1 Hz nerve stimulation. Synaptic depression was characterized by a 46% reduction in the end-plate potential (EPP) amplitude and a 21% decrease in miniature EPP (MEPP) frequency, but no change to MEPP amplitude, indicating a reduction in evoked quantal release. Both the membrane-impermeant NO scavenger cPTIO and the NOS inhibitor L-NAME blocked depression, suggesting that it is induced by NO originating from a source outside the terminal. The depression was dependent on activation of muscle-type, but not neuronal-type, nAChRs and was still observed when Ca2+ release from the sarcoplasmic reticulum and muscle contraction were blocked with dantrolene. These data suggest that the depression depends on transmission, but not muscle contraction. The calcineurin inhibitors cyclosporin A and FK506, as well as ODQ, an inhibitor of NO-sensitive soluble guanylyl cyclase, Rp-8-pCPT-cGMPS, an inhibitor of cGMP-dependent protein kinase, and the calmodulin antagonist phenoxybenzamine also blocked depression. We propose that low frequency synaptic transmission leads to production of NO at the synapse and depression of transmitter release via a cGMP-dependent mechanism. The NO could be generated either directly from the muscle, or possibly from the Schwann cell in response to an unidentified muscle-derived messenger. We showed that the long-lasting depression of transmitter release was due to sustained activity of the NO signalling pathway, and suggest dephosphorylation of NOS by calcineurin as the basis for continued NO production.
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PMID:Postsynaptic production of nitric oxide implicated in long-term depression at the mature amphibian (Bufo marinus) neuromuscular junction. 1524 35

In neurons, neurogranin (Ng) binds calmodulin (CaM), and its binding affinity is reduced by increasing Ca2+, phosphorylation by PKC, or oxidation by oxidants. Ng concentration in the hippocampus of adult mice varied broadly (Ng+/+, 160-370 and Ng+/-, approximately 70-230 pmol/mg); the level in Ng+/+ mice is one of the highest among all neuronal CaM-binding proteins. Among Ng+/- mice, but less apparent in Ng+/+, a significant relationship existed between their hippocampal levels of Ng and performances in the Morris water maze. Ng-/- mice performed poorly in this task; they also displayed deficits in high-frequency-induced long-term potentiation (LTP) in area CA1 of hippocampal slices, whereas low-frequency-induced long-term depression was enhanced. Thus, compared with Ng+/+ mice, the frequency-response curve of Ng-/- shifted to the right. Paired-pulse facilitation and synaptic fatigue during prolonged stimulation at 10 Hz (900 pulses) were unchanged in Ng-/- slices, indicating their normal presynaptic function. Measurements of Ca2+ transients in CA1 pyramidal neurons after weak and strong tetanic stimulations (100 Hz, 400 and 1000 msec, respectively) revealed a significantly greater intracellular Ca2+ ([Ca2+]i) response in Ng+/+ compared with Ng-/- mice, but the decay time constants did not differ. The diminished Ca2+ dynamics in Ng-/- mice are a likely cause of their decreased propensity to undergo LTP. Thus, Ng may promote a high [Ca2+]i by a "mass-action" mechanism; namely, the higher the Ng concentration, the more Ng-CaM complexes will be formed, which effectively raises [Ca2+]i at any given Ca2+ influx. This mechanism provides potent signal amplification in enhancing synaptic plasticity as well as learning and memory.
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PMID:Neurogranin/RC3 enhances long-term potentiation and learning by promoting calcium-mediated signaling. 1556 82

Elevation of intracellular calcium concentration ([Ca(2+)](i)) induces several forms of long-term synaptic plasticity in cerebellar Purkinje cells (PCs). These include (1) long-term depression (LTD) at parallel fiber (PF) to PC synapses, (2) LTD at climbing fiber (CF) to PC synapses, (3) long-term potentiation (LTP) at synapses from inhibitory interneurons (rebound potentiation). The current knowledge about calcium dependency for these forms of synaptic plasticity is described in this chapter. (1) Induction of PF-LTD is dependent on elevation of [Ca(2+)](i), that derives from two distinct sources. One is through voltage-dependent calcium channel (VDCC). A CF stimulation leads to elevation of [Ca(2+)](i) due to activation of VDCCs. The other is from the internal calcium store. PFs stimulation activates metabotropic glutamate receptor subtype 1 (mGluR1). It leads to production of inositol-1,4,5-triphosphate (IP(3)) and diacylglycerol (DG) which cause calcium release from internal stores and activation of protein kinase C, respectively. The conjunctive activation of PF and CF inputs is necessary for PF-LTD. (2) LTD at CF to PC synapses (CF-LTD) is induced by the mechanisms similar to those involved in PF-LTD. CF-LTD requires elevation of [Ca(2+)](i) and activation of the mGluR1 to PKC cascade. (3) Rebound potentiation is induced by transient elevation of [Ca(2+)](i) due to activation of VDCCs or IP3-mediated calcium release from internal stores. Elevation of [Ca(2+)](i) activates calcium/ calmodulin-dependent protein kinase II and leads to persistent up-regulation of postsynaptic GABAA receptor function. At the three types of synapses described above, elevation of [Ca(2+)](i) also causes short-term depression of neurotransmitter release from presynaptic terminals. Recent studies demonstrate that transient elevation of [Ca(2+)](i) produces endocannabinoids in PCs that act retrogradely onto presynaptic terminals and suppress neurotransmitter release.
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PMID:[Calcium dependent forms of synaptic plasticity in cerebellar Purkinje cells]. 1577 59


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