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)

PICK1 is a calcium-sensing, PDZ domain-containing protein that interacts with GluR2 and GluR3 AMPA receptor (AMPAR) subunits and regulates their trafficking. Although PICK1 has been principally implicated in long-term depression (LTD), PICK1 overexpression in CA1 pyramidal neurons causes a CaMK- and PKC-dependent potentiation of AMPAR-mediated transmission and an increase in synaptic GluR2-lacking AMPARs, mechanisms associated with NMDA receptor (NMDAR)-dependent long-term potentiation (LTP). Here, we directly tested whether PICK1 participates in both hippocampal NMDAR-dependent LTP and LTD. We show that the PICK1 potentiation of AMPAR-mediated transmission is NMDAR dependent and fully occludes LTP. Conversely, blockade of PICK1 PDZ interactions or lack of PICK1 prevents LTP. These observations demonstrate an important role for PICK1 in LTP. In addition, deletion of PICK1 or blockade of PICK1 PDZ binding prevented NMDAR-dependent LTD. Thus, PICK1 plays a critical role in bidirectional NMDAR-dependent long-term synaptic plasticity in the hippocampus.
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PMID:An essential role for PICK1 in NMDA receptor-dependent bidirectional synaptic plasticity. 1836 88

Protein kinase C (PKC) is involved in synaptic remodeling, induction of protein synthesis, and many other processes important in learning and memory. Activation of neuronal protein kinase C correlates with, and may be essential for, all phases of learning, including acquisition, consolidation, and reconsolidation. Protein kinase C activation is closely tied to hydrolysis of membrane lipids. Phospholipases C and A2 produce 1,2-diacylglycerol and arachidonic acid, which are direct activators of protein kinase C. Phospholipase C also produces inositol triphosphate, which releases calcium from internal stores. Protein kinase C interacts with many of the same pathways as insulin; therefore, it should not be surprising that insulin signaling and protein kinase C activation can both have powerful effects on memory storage and synaptic remodeling. However, investigating the possible roles of insulin in memory storage can be challenging, due to the powerful peripheral effects of insulin on glucose and the low concentration of insulin in the brain. Although peripheral for insulin, synthesized in the beta-cells of the pancreas, is primarily involved in regulating glucose, small amounts of insulin are also present in the brain. The functions of this brain insulin are inadequately understood. Protein kinase C may also contribute to insulin resistance by phosphorylating the insulin receptor substrates required for insulin signaling. Insulin is also responsible insulin-long term depression, a type of synaptic plasticity that is also dependent on protein kinase C. However, insulin can also activate PKC signaling pathways via PLC gamma, Erk 1/2 MAP kinase, and src stimulation. Taken together, the available evidence suggests that the major impact of protein kinase C and its interaction with insulin in the mature, fully differentiated nervous system appears to be to induce synaptogenesis, enhance memory, reduce Alzheimer's pathophysiology, and stimulate neurorepair.
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PMID:Insulin, PKC signaling pathways and synaptic remodeling during memory storage and neuronal repair. 1840 35

Platelet-derived growth factor (PDGF) beta receptor activation inhibits N-methyl-d-aspartate (NMDA)-evoked currents in hippocampal and cortical neurons via the activation of phospholipase Cgamma, PKC, the release of intracellular calcium, and a rearrangement of the actin cytoskeleton. In the hippocampus, the majority of NMDA receptors are heteromeric; most are composed of 2 NR1 subunits and 2 NR2A or 2 NR2B subunits. Using NR2B- and NR2A-specific antagonists, we demonstrate that PDGF-BB treatment preferentially inhibits NR2B-containing NMDA receptor currents in CA1 hippocampal neurons and enhances long-term depression in an NR2B subunit-dependent manner. Furthermore, treatment of hippocampal slices or cultures with PDGF-BB decreases the surface localization of NR2B but not of NR2A subunits. PDGFbeta receptors colocalize to a higher degree with NR2B subunits than with NR2A subunits. After neuronal injury, PDGFbeta receptors and PDGF-BB are up-regulated and PDGFbeta receptor activation is neuroprotective against glutamate-induced neuronal damage in cultured neurons. We demonstrate that the neuroprotective effects of PDGF-BB are occluded by the NR2B antagonist, Ro25-6981, and that PDGF-BB promotes NMDA signaling to CREB and ERK1/2. We conclude that PDGFbetaR signaling, by preferentially targeting NR2B receptors, provides an important mechanism for neuroprotection by growth factors in the central nervous system.
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PMID:Platelet-derived growth factor selectively inhibits NR2B-containing N-methyl-D-aspartate receptors in CA1 hippocampal neurons. 1910 10

There are two major forms of long-term depression (LTD) of synaptic transmission in the central nervous system that require activation of either N-methyl-D-aspartate receptors (NMDARs) or metabotropic glutamate receptors (mGluRs). In synapses in the perirhinal cortex, we have directly compared the Ca(2+) signaling mechanisms involved in NMDAR-LTD and mGluR-LTD. While both forms of LTD involve Ca(2+) release from intracellular stores, the Ca(2+) sensors involved are different; NMDAR-LTD involves calmodulin, while mGluR-LTD involves the neuronal Ca(2+) sensor (NCS) protein NCS-1. In addition, there is a specific requirement for IP3 and PKC, as well as protein interacting with C kinase (PICK-1) in mGluR-LTD. NCS-1 binds directly to PICK1 via its BAR domain in a Ca(2+)-dependent manner. Furthermore, the NCS-1-PICK1 association is stimulated by activation of mGluRs, but not NMDARs, and introduction of a PICK1 BAR domain fusion protein specifically blocks mGluR-LTD. Thus, NCS-1 plays a distinct role in mGluR-LTD.
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PMID:Metabotropic glutamate receptor-mediated LTD involves two interacting Ca(2+) sensors, NCS-1 and PICK1. 1910 14

The primary auditory cortex is subject to the modulation of numerous neurotransmitters including norepinephrine (NE), which has been shown to decrease cellular excitability by yet unclear mechanisms. We investigated the possibility that NE directly affects excitatory glutamatergic synapses. We found that bath applications of NE (20 microM) decreased glutamatergic excitatory post-synaptic currents (EPSCs) in all cortical layers. Changes in the kinetics of synaptic EPSCs, invariance of pair pulse ratio and of the coefficient-of-variation, together with the decrease of responses to pressure-application of AMPA (500 microM), indicated the postsynaptic nature of the adrenergic effect. Pharmacological experiments suggested that the NE-induced depression of EPSCs is caused by the activation of alpha1 adrenoceptors, PLC, and a Ca(2+)-independent PKC. We speculate that the decrease in temporal cortex excitability might promote a posterior-to-anterior shift in cortical activation together with a decrease in spontaneous background activity, resulting eventually in more effective sensory processing.
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PMID:Norepinephrine homogeneously inhibits alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate- (AMPAR-) mediated currents in all layers of the temporal cortex of the rat. 1935 50

Regulation of surface insertion and internalization of AMPA and NMDA receptors has emerged as a key mechanism for the control of synaptic strength. Regulatory elements for synaptic kainate receptors (KARs) are, however, largely undetermined. We have found that SNAP25 is critical for the synaptic removal of KARs, acting via GluK5 (i.e., KA2) subunits. SNAP25 coimmunoprecipitates with protein complexes containing PICK1, GRIP1, and GluK5 and colocalizes with GluK5 in both hippocampal neurons and transfected HEK293 cells. In hippocampal slices, purified SNAP25 antibodies and blocking peptides caused a GluK5-dependent run-up of KARs-mediated EPSC (EPSC(KAR)) recorded from CA3 pyramidal neurons when included in the patch pipette and prevented activity-dependent long-term depression of EPSC(KAR). As EPSC(KAR) LTD, SNAP25/PICK1/GluK5 interactions are dynamically regulated by PKC.
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PMID:A role for SNAP25 in internalization of kainate receptors and synaptic plasticity. 1967 75

The ability of T-lymphocytes to recognize antigens and transduce signals to the nucleus successfully is a key component in the initiation and maintenance of an immune response. The present study addressed the expression status of the signal-transducing proteins in relation to the immune impairment in cervical cancer patients. Immune response was measured by evaluating lymphocyte subpopulations CD3(+), CD4(+), and CD8(+), using flowcytometry, natural killer cell activity, using the single-cell cytotoxicity assay, lymphocyte function, using mitogenic response to PHA and T-cell activation following anti-CD3 stimulation, and production of IL-2. Expression of the T-cell signal transduction proteins, TCR-zeta, CD3-epsilon, zap-70, p(56)lck, PKC, NFkappabeta p50, Rel-A, Rel-B, and c-rel, was evaluated by using Western blot assay. A generalized depression of the immune response with respect to the different parameters evaluated was observed. Exogenous interleukin-2 (IL-2) could increase the response in all the controls and in 30% of the patients to different degrees varying from 10% to 90%. Low levels of the signaling molecules (TCR-zeta, CD3-epsilon, zap-70, p(56)lck, and PKC) and impairment in the transduction of NFkappabeta components (p50, Rel-A, Rel-B, and c-rel) to the nuclei were observed in these lymphocytes. Decreased CD4(+)/CD8(+) ratio with an increase in suppressor cells, reduced lymphocyte proliferation, and production of IL-2 suggest a defective immune regulation in cervical cancer. Impairment in the translocation of NFkappabeta p50, Rel-A, and Rel-B to the nucleus and the reduced levels of signal-transducing proteins might be responsible for the decreased production of IL-2 and immune impairment in cervical cancer patients.
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PMID:Signaling defects and functional impairment in T-cells from cervical cancer patients. 2002 46

To investigate the role of M1 muscarininc acetylcholine receptors (m1 receptors) in metabotropic glutamate receptor (mGluR)-mediated long-term depression (LTD), we produced mouse lines in which deletion of the m1 gene is restricted to the forebrain (FB-m1KO) or hippocampal CA3 pyramidal neurons (CA3-m1KO). Stimulation in FB-m1KO hippocampal slices resulted in excitatory postsynaptic potentials and long-term synaptic plasticity (long-term potentiation and LTD) similar to controls. The mice were deficient in (S)-3,5-dihydroxyphenylglycine hydrate (DHPG)-induced mGluR LTD, which correlated with a presynaptic increase in the release of neurotransmitters. Protein kinase C (PKC) activity, which is downstream from both mGluRs and m1 receptors, was reduced in CA3 but not in CA1. The presynaptic requirement of m1 receptors was confirmed by the lack of DHPG-induced mGluR LTD in the CA1 of slices from CA3-m1KO mice. mGluR LTD was rescued by stimulating PKC activity pharmacologically in CA3-m1KO mice. These data confirm a role for PKC activation in presynaptic induction of mGluR LTD and distinguish between the roles of mGluRs and m1 receptors.
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PMID:Presynaptic m1 muscarinic receptors are necessary for mGluR long-term depression in the hippocampus. 2008 Jun 9

In this study, we show the crucial roles of lipid signaling in long-term depression (LTD), that is, synaptic plasticity prevailing in cerebellar Purkinje cells. In mouse brain slices, we found that cPLA(2)alpha knockout blocked LTD induction, which was rescued by replenishing arachidonic acid (AA) or prostaglandin (PG) D(2) or E(2). Moreover, cyclooxygenase (COX)-2 inhibitors block LTD, which is rescued by supplementing PGD(2)/E(2). The blockade or rescue occurs when these reagents are applied within a time window of 5-15 min following the onset of LTD-inducing stimulation. Furthermore, PGD(2)/E(2) facilitates the chemical induction of LTD by a PKC activator but is unable to rescue the LTD blocked by a PKC inhibitor. We conclude that PGD(2)/E(2) mediates LTD jointly with PKC, and suggest possible pathways for their interaction. Finally, we demonstrate in awake mice that cPLA(2)alpha deficiency or COX-2 inhibition attenuates short-term adaptation of optokinetic eye movements, supporting the view that LTD underlies motor learning.
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PMID:Lipid signaling in cytosolic phospholipase A2alpha-cyclooxygenase-2 cascade mediates cerebellar long-term depression and motor learning. 2013 5

Associative long-term depression (LTD) in the hippocampus is a form of spike time-dependent synaptic plasticity that is induced by the asynchronous pairing of postsynaptic action potentials and EPSPs. Although metabotropic glutamate receptors (mGluRs) and postsynaptic Ca(2+) signaling have been suggested to mediate associative LTD, mechanisms are unclear further downstream. Here we show that either mGluR1 or mGluR5 activation is necessary for LTD induction, which is therefore mediated by group I mGluRs. Inhibition of postsynaptic phospholipase C, inositol-1,4,5-trisphosphate, and PKC prevents associative LTD. Activation of PKC by a phorbol ester causes a presynaptic potentiation of synaptic responses and facilitates LTD induction by a postsynaptic mechanism. Lithium, an inhibitor of the PKC pathway, inhibits LTD and the presynaptic and postsynaptic effects of the phorbol ester. Furthermore, LTD is sensitive to the postsynaptic application of synthetic peptides that inhibit the interaction of AMPA receptors with PDZ domains, suggesting an involvement of protein interacting with C-kinase 1 (PICK1)-mediated receptor endocytosis. Finally, enhanced PKC phosphorylation, induced by behavioral stress, is associated with enhanced LTD. Both increased PKC phosphorylation and stress-induced LTD facilitation can be reversed by lithium, indicating that this clinically used mood stabilizer may act on synaptic depression via PKC modulation. These data suggest that PKC mediates the expression of associative LTD via the PICK1-dependent internalization of AMPA receptors. Moreover, modulation of the PKC activity adjusts the set point for LTD induction in a behavior-dependent manner.
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PMID:Coincidence detection and stress modulation of spike time-dependent long-term depression in the hippocampus. 2044 48


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