Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The interaction of PDZ domain-containing proteins with the C termini of alpha-amino-3-hydroxy-5-methylisoxazolepropionate (AMPA) receptors has been suggested to be important in the regulation of receptor targeting to excitatory synapses. Recent studies have shown that the rapid internalization of AMPA receptors at synapses may mediate, at least in part, the expression of long-term depression (LTD). We have previously shown that phosphorylation of Ser-880 on the AMPA receptor GluR2 subunit differentially regulated the interaction of GluR2 with the PDZ domain-containing proteins GRIP1 and PICK1. Here, we show that induction of LTD in hippocampal slices increases phosphorylation of Ser-880 within the GluR2 C-terminal PDZ ligand, suggesting that the modulation of GluR2 interaction with GRIP1 and PICK1 may regulate AMPA receptor internalization during LTD. Moreover, postsynaptic intracellular perfusion of GluR2 C-terminal peptides that disrupt GluR2 interaction with PICK1 inhibit the expression of hippocampal LTD. These results suggest that the interaction of GluR2 with PICK1 may play a regulatory role in the expression of LTD in the hippocampus.
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PMID:Interaction of the AMPA receptor subunit GluR2/3 with PDZ domains regulates hippocampal long-term depression. 1157 7

The cytoplasmic C termini of AMPA receptor subunits contain PDZ (postsynaptic density 95/Discs large/zona occludens 1) ligand domains that can control their synaptic trafficking during plasticity. The glutamate receptor subunit 2 (GluR2) PDZ ligand domain can be phosphorylated at serine 880 (S880), and this disrupts interactions with GRIP/ABP (glutamate receptor-interacting protein/AMPA-binding protein) but not with PICK1 (PKC-interacting protein 1). Here, the impact of GluR2 S880 phosphorylation on synaptic transmission and plasticity was explored by expressing, in hippocampal slice cultures, GluR2 subunits containing point mutations that mimic or prevent phosphorylation at this residue. Our results indicate that mimicking GluR2 S880 phosphorylation excludes these receptors from synapses, depresses transmission, and partially occludes long-term depression (LTD). Conversely, mutations that prevent phosphorylation reduce LTD. Disruption of the interaction between GluR2 and GRIP/ABP by S880 phosphorylation may thus facilitate removal of synaptic AMPA receptors and mediate some forms of activity-dependent synaptic depression.
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PMID:Glutamate receptor subunit 2 Serine 880 phosphorylation modulates synaptic transmission and mediates plasticity in CA1 pyramidal cells. 1453 56

Cerebellar long-term depression (LTD) is a persistent attenuation of synaptic transmission at the parallel fiber-Purkinje cell synapse mediated by the removal of GluR2 subunit-containing alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. The removal of AMPA receptors requires protein kinase C phosphorylation of the GluR2 subunit within its carboxyl-terminal PSD-95/Discs Large/Zona Occludens-1 (PDZ) ligand and binding of the PDZ domain-containing protein, PICK1. The sequence of the GluR2 subunit is similar to that of the GluR3 and GluR4c subunits, which also contain PDZ ligands and protein kinase C consensus sites. Although GluR3 and GluR4c are also expressed in Purkinje cells, we have previously shown that cerebellar LTD is absent in GluR2(-/-) mice, suggesting that these subunits are unable to substitute functionally for GluR2. Here, we examine the apparent difference in the regulation of these AMPA receptor subunits by attempting to rescue LTD in GluR2(-/-) Purkinje cells with WT and mutant GluR2 and GluR3 subunits. Our results show that the selective interaction of the GluR2 subunit with the N-ethylmaleimide-sensitive factor protein is required for synaptic, but not extrasynaptic, incorporation of AMPA receptors as well as for their competence to undergo LTD. In addition, perfusion of a synthetic peptide that acutely disrupts the interaction of GluR2 with N-ethylmaleimide-sensitive factor selectively depletes GluR2-containing receptors from synapses and occludes LTD. These findings demonstrate that interaction of AMPA receptors with N-ethylmaleimide-sensitive factor plays a critical role in incorporation of AMPA receptors into synapses and for their subsequent removal during cerebellar LTD.
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PMID:N-ethylmaleimide-sensitive factor is required for the synaptic incorporation and removal of AMPA receptors during cerebellar long-term depression. 1560 60

Kainate receptors (KARs) have been shown to be involved in hippocampal mossy fiber long-term potentiation (LTP); however, it is not known if KARs are involved in the induction or expression of long-term depression (LTD), the other major form of long-term synaptic plasticity. Here we describe LTD of KAR-mediated synaptic transmission (EPSC(KA) LTD) in perirhinal cortex layer II/III neurons that is distinct from LTD of AMPAR-mediated transmission, which also coexists at the same synapses. Induction of EPSC(KA) LTD requires a rise in postsynaptic Ca(2+) but is independent of NMDARs or T-type voltage-gated Ca(2+) channels; however, it requires synaptic activation of inwardly rectifying KARs and release of Ca(2+) from stores. The synaptic KARs are regulated by tonically activated mGluR5, and expression of EPSC(KA) LTD occurs via a mechanism involving mGluR5, PKC, and PICK1 PDZ domain interactions. Thus, we describe the induction and expression mechanism of a form of synaptic plasticity, EPSC(KA) LTD.
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PMID:Long-term depression of kainate receptor-mediated synaptic transmission. 1638 42

The targeting and surface expression of membrane proteins are critical to their functions. In neurons, synaptic targeting and surface expression of AMPA-type glutamate receptors were found to be critical for synaptic plasticity such as long-term potentiation and long-term depression (LTD). PICK1 (protein interacting with C kinase 1) is a cytosolic protein that interacts with many membrane proteins, including AMPA receptors via its PDZ (postsynaptic density-95/Discs large/zona occludens-1) domain. Its interactions with membrane proteins regulate their subcellular targeting and surface expression. However, the mechanism by which PICK1 regulates protein trafficking has not been fully elucidated. Here, we show that PICK1 directly binds to lipids, mainly phosphoinositides, via its BAR (Bin/amphiphysin/Rvs) domain. Lipid binding of the PICK1 BAR domain is positively regulated by its PDZ domain and negatively regulated by its C-terminal acidic domain. Mutation of critical residues of the PICK1 BAR domain eliminates its lipid-binding capability. Lipid binding of PICK1 controls the subcellular localization of the protein, because BAR domain mutant of PICK1 has diminished synaptic targeting compared with wild-type PICK1. In addition, the BAR domain mutant of PICK1 does not cluster AMPA receptors. Moreover, wild-type PICK1 enhances synaptic targeting of AMPA receptors, whereas the BAR domain mutant of PICK1 fails to do so. The BAR domain mutant of PICK1 loses its ability to regulate surface expression of the AMPA receptors and impairs expression of LTD in hippocampal neurons. Together, our findings indicate that the lipid binding of the PICK1 BAR domain is important for its synaptic targeting, AMPA receptor trafficking, and synaptic plasticity.
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PMID:Lipid binding regulates synaptic targeting of PICK1, AMPA receptor trafficking, and synaptic plasticity. 1680 37

Cerebellar long-term depression (LTD) is a major form of synaptic plasticity that is thought to be critical for certain types of motor learning. Phosphorylation of the AMPA receptor subunit GluR2 on serine-880 as well as interaction of GluR2 with PICK1 have been suggested to contribute to the endocytic removal of postsynaptic AMPA receptors during LTD. Here, we show that targeted mutation of PICK1, the GluR2 C-terminal PDZ ligand, or the GluR2 PKC phosphorylation site eliminates cerebellar LTD in mice. LTD can be rescued in cerebellar cultures from mice lacking PICK1 by transfection of wild-type PICK1 but not by a PDZ mutant or a BAR domain mutant deficient in lipid binding, indicating the importance of these domains in PICK1 function. These results demonstrate that PICK1-GluR2 PDZ-based interactions and GluR2 phosphorylation are required for LTD expression in the cerebellum.
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PMID:Targeted in vivo mutations of the AMPA receptor subunit GluR2 and its interacting protein PICK1 eliminate cerebellar long-term depression. 1654 22

The glutamate receptor delta2 subunit (GluRdelta2) is selectively expressed in cerebellar Purkinje neurons (PNs) and is involved in the long-term depression (LTD). However, little is known about the mechanism of its action. Acute expression of the wild-type GluRdelta2 in the GluRdelta2-deficient PN rescued the induction of LTD, suggesting the direct role of GluRdelta2 in LTD. To identify the critical region of GluRdelta2 necessary for LTD, we constructed and expressed various mutant GluRdelta2 proteins in the GluRdelta2-deficient PNs. The mutant GluRdelta2 possessing the membrane-proximal 21 aa residues in the C-terminal cytoplasmic region rescued the induction of LTD, whereas the mutant with membrane-proximal 13 aa failed. In addition, overexpression of 865 approximately 871 aa of GluRdelta2 (corresponding to membrane-proximal 14-20 aa) fused to EGFP (enhanced green fluorescent protein) suppressed LTD in a wild-type PN. These results suggest that 865 approximately 871 aa of GluRdelta2 play an essential role in LTD. We next identified protein interacting with C kinase 1 (PICK1) as a molecule interacting with the membrane-proximal C-terminal region of GluRdelta2 by yeast two-hybrid screening. PICK1 plays an essential role in LTD. It colocalized with GluRdelta2 at spines of PNs, and immunoprecipitation assays showed that GluRdelta2 bound to PICK1 mainly through 865-871 aa. These results indicate that 865-871 aa of GluRdelta2 are essential for both LTD and interaction with PICK1, and suggest that interaction between GluRdelta2 and PICK1 might be critical for the induction of LTD.
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PMID:Membrane-proximal region of glutamate receptor delta2 subunit is critical for long-term depression and interaction with protein interacting with C kinase 1 in a cerebellar Purkinje neuron. 1659 15

Filamentous actin binding protein neurabin I (NrbI) targets protein phosphatase-1 (PP1) to specific postsynaptic microdomains, exerting critical control over AMPA receptor (AMPAR)-mediated synaptic transmission. NrbI-targeted synaptic PP1, which promotes synaptic depression upon long-term depression (LTD) stimuli, serves to prevent synaptic depression under basal conditions. The present studies investigate this opposite regulation of AMPAR trafficking during basal synaptic transmission and LTD by expressing NrbI or NrbI mutant, which is defective in PP1 binding, in hippocampal slice or neuron cultures. We find that expression of the NrbI mutant to interfere with PP1 targeting dramatically reduces basal synaptic transmission, which is correlated with the reduction in surface expression of AMPA subtype glutamate receptor (GluR) 1 and GluR2 subunits. Biochemical analysis demonstrates that the NrbI mutant selectively increases the phosphorylation of GluR2 at C-terminal consensus PKC site, serine 880, which is known to favor GluR2 interaction with PDZ (postsynaptic density 95/Discs large/zona occludens 1) protein PICK1 (protein interacting with C kinase-1). Inhibition of PKC activity or GluR2-PICK1 interaction completely reverses the synaptic depression in neurons expressing the NrbI mutant, suggesting that NrbI-targeted synaptic PP1 stabilizes the basal transmission by negatively controlling PKC phosphorylation of GluR2 and the subsequent PICK1-mediated decrease in GluR2-containing AMPAR surface expression. Distinct from basal transmission, blocking GluR2-PICK1 interaction or PKC activity produces minimal effects on LTD in NrbI-expressing neurons. Instead, NrbI-targeted PP1 facilitates LTD by dephosphorylating GluR1 at both serine 845 and serine 831, with GluR2 serine 880 phosphorylation unaltered. Our studies thus elucidate that NrbI-targeted PP1, in response to distinct synaptic activities, regulates the synaptic trafficking of specific AMPAR subunits.
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PMID:Differential regulation of AMPA receptor trafficking by neurabin-targeted synaptic protein phosphatase-1 in synaptic transmission and long-term depression in hippocampus. 1746 80

Many central excitatory synapses undergo developmental alterations in the molecular and biophysical characteristics of postsynaptic ionotropic glutamate receptors via changes in subunit composition. Concerning AMPA receptors (AMPARs), glutamate receptor 2 subunit (GluR2)-containing, Ca2+-impermeable AMPARs (CI-AMPARs) prevail at synapses between mature principal neurons; however, accumulating evidence indicates that GluR2-lacking, Ca2+-permeable AMPARs (CP-AMPARs) contribute at these synapses early in development. Here, we used a combination of imaging and electrophysiological recording techniques to investigate potential roles for CP-AMPARs at developing hippocampal mossy fiber-CA3 pyramidal cell (MF-PYR) synapses. We found that transmission at nascent MF-PYR synapses is mediated by a mixed population of CP- and CI-AMPARs as evidenced by polyamine-dependent inwardly rectifying current-voltage (I-V) relationships, and partial philanthotoxin sensitivity of synaptic events. CP-AMPAR expression at MF-PYR synapses is transient, being limited to the first 3 postnatal weeks. Moreover, the expression of CP-AMPARs is regulated by the PDZ (postsynaptic density-95/Discs large/zona occludens-1) domain-containing protein interacting with C kinase 1 (PICK1), because MF-PYR synapses in young PICK1 knock-out mice are philanthotoxin insensitive with linear I-V relationships. Strikingly, MF-PYR transmission via CP-AMPARs is selectively depressed during depolarization-induced long-term depression (DiLTD), a postsynaptic form of MF-PYR plasticity observed only at young MF-PYR synapses. The selective depression of CP-AMPARs during DiLTD was evident as a loss of postsynaptic CP-AMPAR-mediated Ca2+ transients in PYR spines and reduced rectification of MF-PYR synaptic currents. Preferential targeting of CP-AMPARs during DiLTD is further supported by a lack of DiLTD in young PICK1 knock-out mice. Together, these findings indicate that the transient participation of CP-AMPARs at young MF-PYR synapses dictates the developmental window to observe DiLTD.
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PMID:Developmental expression of Ca2+-permeable AMPA receptors underlies depolarization-induced long-term depression at mossy fiber CA3 pyramid synapses. 1795 8

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


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