Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Monocular deprivation leads to clear physiological and anatomical changes in the visual cortex known as ocular dominance plasticity. Protein kinase A (PKA) is necessary for ocular dominance plasticity, while protein kinase G (PKG) is not. We have now tested the role of PKA and PKG in long-term potentiation (LTP) and long-term depression (LTD). We have shown that PKA inhibitors have a major effect on both LTP and LTD in the visual cortical slices, whereas a PKG inhibitor affects LTP but not LTD. The PKA activator, 8-chloroadenosine-3',5'-monophosphorothioate, Sp-isomer (Sp-8-Cl-cAMPS), by itself induces a slowly rising form of LTP, which is occluded by theta-burst stimulation (TBS)-induced LTP. These results support the point that the PKA signaling pathway is crucial for neuronal plasticity in visual cortex, and the dissociation of the role of PKA and PKG in long-term synaptic plasticity in the visual cortex suggests that LTP alone is not sufficient to support ocular dominance plasticity, or LTD plays a more fundamental role than LTP in ocular dominance plasticity.
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PMID:Roles of protein kinase A and protein kinase G in synaptic plasticity in the visual cortex. 1285 73

The neurotransmitter serotonin (5-HT) plays an important role in memory encoding in Aplysia. Early evidence showed that during sensitization, 5-HT activates a cyclic AMP-protein kinase A (cAMP-PKA)-dependent pathway within specific sensory neurons (SNs), which increases their excitability and facilitates synaptic transmission onto their follower motor neurons (MNs). However, recent data suggest that serotonergic modulation during sensitization is more complex and diverse. The neuronal circuits mediating defensive reflexes contain a number of interneurons that respond to 5-HT in ways opposite to those of the SNs, showing a decrease in excitability and/or synaptic depression. Moreover, in addition to acting through a cAMP-PKA pathway within SNs, 5-HT is also capable of activating a variety of other protein kinases such as protein kinase C, extracellular signal-regulated kinases, and tyrosine kinases. This diversity of 5-HT responses during sensitization suggests the presence of multiple 5-HT receptor subtypes within the Aplysia central nervous system. Four 5-HT receptors have been cloned and characterized to date. Although several others probably remain to be characterized in molecular terms, especially the Gs-coupled 5-HT receptor capable of activating cAMP-PKA pathways, the multiplicity of serotonergic mechanisms recruited into action during learning in Aplysia can now be addressed from a molecular point of view.
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PMID:Multiple serotonergic mechanisms contributing to sensitization in aplysia: evidence of diverse serotonin receptor subtypes. 1455 10

We have previously reported that dopamine (DA) depresses non-NMDA receptor-mediated glutamatergic transmission in the rat parabrachial nucleus (PBN), an interface between brainstem and forebrain that is implicated in autonomic regulation. This work examined cellular signalling pathways that might underlie this DA-induced synaptic depression. Direct activation of adenylyl cyclase with 10 microM forskolin increased the evoked EPSC but did not occlude DA-induced EPSC depression. Similarly, a preferential protein kinase A inhibitor, H-7 (10 microM), did not block DA's synaptic effects. Incubation of slices with cholera toxin (CTX; 1 microgram/ml) or pertussis toxin (PTX; 0.5 microgram/ml) for 20 h, procedures used to irreversibly activate or disable the G(s) and G(i) proteins, respectively, did not change DA's effects. The putative phospholipase C inhibitor, U-73122 (10 microM) and its inactive analogue U-73343 (10 microM) did not alter DA-induced reduction in the EPSCs. Alterations in signalling molecules downstream of phospholipase C including depleting internal calcium stores by thapsigargin and cyclopiazonic acid and blocking protein kinase C with chelerythrine, had no effect on DA-induced synaptic depression. Furthermore, DA's depression of the non-NMDA response was not blocked by APV, an NMDA receptor antagonist. Finally, DA depressed evoked, pharmacologically isolated NMDA receptor-mediated synaptic responses while increasing NMDA-induced inward currents in the PBN. These results indicate that DA-induced synaptic effects in the PBN are not through the activation of cholera or pertussis toxin sensitive G proteins. Furthermore, it does not employ the adenylyl cyclase-cAMP-PKA cascade, the phospholipase C signalling pathway and NMDA receptor-coupled mechanisms to depress excitatory synaptic transmission in the PBN.
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PMID:Dopamine-induced synaptic depression in the parabrachial nucleus is independent of CTX- and PTX-sensitive G-proteins, PKA and PLC signalling pathways. 1467 13

Correlated pre- and postsynaptic activity that induces long-term potentiation is known to induce a persistent enhancement of the intrinsic excitability of the presynaptic neuron. Here we report that, associated with the induction of long-term depression in hippocampal cultures and in somatosensory cortical slices, there is also a persistent reduction in the excitability of the presynaptic neuron. This reduction requires postsynaptic Ca(2+) elevation and presynaptic PKA- and PKC-dependent modification of slow-inactivating K(+) channels. The bidirectional changes in neuronal excitability and synaptic efficacy exhibit identical requirements for the temporal order of pre- and postsynaptic activation but reflect two distinct aspects of activity-induced modification of neural circuits.
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PMID:Bidirectional modification of presynaptic neuronal excitability accompanying spike timing-dependent synaptic plasticity. 1474 Nov 6

Long-term depression (LTD) induction relies upon receptor cross-talk between group I and group II metabotropic glutamate receptors (mGluRs) in perirhinal cortex. The molecular mechanism of this mGluR interplay is not clear. Here, we show that the mGluR subtypes postulated to be involved in this mechanism are developmentally regulated and mGluR2 has a preferential role over mGluR3 in the synergistic interaction with mGluR5. We have identified a >70% reduction in basal cAMP levels following mGluR2 stimulation, which could lead to increased mGluR5 function via reduced PKA mediated phosphorylation and decreased desensitisation of mGluR5. To further investigate the roles of mGluRs in downstream intracellular signalling, we have examined the effects of mGluRs on the phosphorylation state of cAMP response element-binding protein (CREB). Both group I and group II agonists increased the phosphorylation of CREB, which indicates a cAMP- and PKA-independent signalling mechanism. These results suggest a convergence of signalling mechanisms from surface mGluRs to CREB-mediated transcription.
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PMID:Metabotropic glutamate receptor signalling in perirhinal cortical neurons. 1501 44

Activation of group I and group II metabotropic glutamate receptors (mGluRs) is thought to be required for long-term depression (LTD) of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor-mediated synaptic transmission in the perirhinal cortex. However, little is known about how activation of mGluRs leads to this form of synaptic plasticity. AMPA receptor phosphorylation has been implicated in several forms of modulation of synaptic transmission. In the CA1 area of the hippocampus, N-methyl-d-aspartate (NMDA) receptor-dependent LTD is associated with the reduced phosphorylation of the GluR1 AMPA receptor subunit at serine 845 (GluR1-S845). Immunoblot analysis of perirhinal cortical neurons using GluR1 and GluR1-S845 phosphorylation state specific antibodies showed that stimulation of adenylyl cyclase (AC) with forskolin (FSK) dramatically increased PKA-mediated phosphorylation of GluR1-S845. However, selective or simultaneous application of mGluR5 agonist (S)-3,5-dihydroxyphenylglycine (CHPG) and mGluR2/3 agonist (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG IV) did not produce detectable changes in GluR1-S845 phosphorylation. These results indicate that in the perirhinal cortex mGluR activation does not alter the phosphorylation state of GluR1-S845. Therefore, it is likely that the process involved in the modification of AMPA receptors in mGluR activation dependent LTD in the perirhinal cortex is mechanistically distinct from NMDA receptor-mediated LTD described in hippocampal neurons.
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PMID:Activation of metabotropic glutamate receptors does not alter the phosphorylation state of GluR1 AMPA receptor subunit at serine 845 in perirhinal cortical neurons. 1553 Nov 3

The latest and most generative biological theories of major depression center on two major hypotheses. The first focuses on the concept that hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis leads to many of the pathological changes in the brain that accompany major depression. The second posits that neurogenesis leads to the repair of depression-related injuries. These two hypotheses are complementary: the former alludes to the etiology or consequences of depression, while the latter suggests mechanisms of antidepressant action. Significant crosstalk occurs between these two systems at many levels. Protein kinase A (PKA) may play an important role in this crosstalk at the intracellular level of signaling cascades. PKA is involved in the formation of long-term potentiation and fear conditioning in response to stress. Chronic stress leads to the suppression of hippocampal activity, which may cause the hyperactivity of the HPA axis during melancholic depression. PKA is also involved in the stimulation of hippocampal neurogenesis after antidepressant treatment. In theory, neurogenesis may lead to the restoration of hippocampal function, and this may be the mechanism that leads to antidepressant-mediated normalization of HPA hyperactivity. Thus, PKA is active during processes that potentially lead to depression and other processes that lead to the resolution of the illness. These opposing processes may be mediated by separate PKA isozymes that activate two distinct pathways. This review highlights the dual role of this enzyme in two biological hypotheses pertaining to depression and its treatment.
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PMID:Protein kinase a in major depression: the link between hypothalamic-pituitary-adrenal axis hyperactivity and neurogenesis. 1557 20

Cardioprotection by intermittent high-altitude (IHA) hypoxia against ischemia-reperfusion (I/R) injury is associated with Ca(2+) overload reduction. Phospholamban (PLB) phosphorylation relieves cardiac sarcoplasmic reticulum (SR) Ca(2+)-pump ATPase, a critical regulator in intracellular Ca(2+) cycling, from inhibition. To test the hypothesis that IHA hypoxia increases PLB phosphorylation and that such an effect plays a role in cardioprotection, we compared the time-dependent changes in the PLB phosphorylation at Ser(16) (PKA site) and Thr(17) (CaMKII site) in perfused normoxic rat hearts with those in IHA hypoxic rat hearts submitted to 30-min ischemia (I30) followed by 30-min reperfusion (R30). IHA hypoxia improved postischemic contractile recovery, reduced the maximum extent of ischemic contracture, and attenuated I/R-induced depression in Ca(2+)-pump ATPase activity. Although the PLB protein levels remained constant during I/R in both groups, Ser(16) phosphorylation increased at I30 and 1 min of reperfusion (R1) but decreased at R30 in normoxic hearts. IHA hypoxia upregulated the increase further at I30 and R1. Thr(17) phosphorylation decreased at I30, R1, and R30 in normoxic hearts, but IHA hypoxia attenuated the depression at R1 and R30. Moreover, PKA inhibitor H89 abolished IHA hypoxia-induced increase in Ser(16) phosphorylation, Ca(2+)-pump ATPase activity, and the recovery of cardiac performance after ischemia. CaMKII inhibitor KN-93 also abolished the beneficial effects of IHA hypoxia on Thr(17) phosphorylation, Ca(2+)-pump ATPase activity, and the postischemic contractile recovery. These findings indicate that IHA hypoxia mitigates I/R-induced depression in SR Ca(2+)-pump ATPase activity by upregulating dual-site PLB phosphorylation, which may consequently contribute to IHA hypoxia-induced cardioprotection against I/R injury.
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PMID:Role of dual-site phospholamban phosphorylation in intermittent hypoxia-induced cardioprotection against ischemia-reperfusion injury. 1563 15

To maintain synaptic transmission during intense neuronal activities, the synaptic vesicle (SV) pool at release sites is effectively replenished by recruitment of SVs from the reserve pool and/or by endocytosis. The authors have studied dynamics of SVs using a fluorescence dye, FM1-43, which is incorporated into SVs during endocytosis and released by exocytosis. Drosophila is one of the most suitable preparations for genetic and pharmacological analyses, and this provides a useful model system. The authors found at the neuromuscular junctions of Drosophila that exocytosis and endocytosis of SVs are triggered by Ca(2+) influx through distinct routes and that selective inhibition of exocytosis or endocytosis resulted in depression of synaptic transmission with a distinct time course. They identified two SV pools in a single presynaptic bouton. The exo/endo cycling pool (ECP) is loaded with FM1-43 during low-frequency stimulation and locates close to release sites in the periphery of boutons, whereas the reserve pool (RP) is loaded and unloaded only during high-frequency stimulation and resides primarily in the center of boutons. The size of ECP closely correlates with the quantal content of evoked release, suggesting that SVs in the ECP are primarily involved in synaptic transmission. SVs in the RP are recruited to synaptic transmission by a process involving the cAMP/PKA cascade during high-frequency stimulation. Cytochalasin D blocked this recruitment process, suggesting involvement of filamentous actin. Endocytosed SVs replenish the ECP during stimulation and the RP after tetanic stimulation. Replenishment of the ECP depends on Ca(2+) influx from external solutions, and that of the RP is initiated by Ca(2+) release from internal stores. Thus, SV dynamics is closely involved in modulation of synaptic efficacy and influences synaptic plasticity.
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PMID:Exocytosis and endocytosis of synaptic vesicles and functional roles of vesicle pools: lessons from the Drosophila neuromuscular junction. 1574 82

IKs has been considered the potassium current most responsible for adrenergic/cAMP-mediated changes in cardiac repolarization during stress. Increasing biochemical, electrophysiological and genetic evidence however, points to a role for hERG/IKr in beta-adrenergic responses. Elevations of cAMP as seen in beta-adrenergic stimulation can result in PKA-dependent phosphorylation of hERG and direct binding of cAMP to the channel protein. Generally, there is a suppression of current density due to the channel phosphorylation. We recently identified a novel protein-protein interaction between hERG and the adaptor protein 14-3-3epsilon. Interaction sites exist on both N- and C-termini of hERG and the interaction is dynamic, requiring phosphorylation of the channel by PKA. When both sites bind to 14-3-3 proteins there is an acceleration and augmentation of current activation in contrast to the depression of current with phosphorylation alone. When sufficient 14-3-3 is available the phosphorylation state of the channel is stabilized and prolonged. Thus, 14-3-3 interactions with hERG provide a unique mechanism for plasticity in the autonomic control of stress-dependent regulation of cardiac membrane excitability. Here, we summarize our findings and report on our further efforts to analyse interactions between the native channel protein and 14-3-3 in cardiac myocytes.
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PMID:Dynamic control of hERG/I(Kr) by PKA-mediated interactions with 14-3-3. 1605 Feb 63


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