PDZ Proteins Interacting with C-Terminal GluR2/3 Are Involved in a PKC-Dependent Regulation of AMPA Receptors at Hippocampal Synapses

Daw, Michael I.; Chittajallu, Ramesh; Bortolotto, Zuner A.; Dev, Kumlesh K.; Duprat, Fabrice; Henley, Jeremy M.; Collingridge, Graham L.; Isaac, John T.R.

doi:10.1016/s0896-6273(00)00160-4

Cited by 300 publications

(365 citation statements)

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“…particular postsynaptic roles. For example, Pick 1 and GRIP1, which both interact with the C-terminal terminal of the AMPA receptor subunits, GluR2/3, are involved in their internalization and synaptic stabilization (Dong et al 1999;Dev et al 1999;Chung et al 2000;Daw et al 2000;El-Husseini et al 2000;Osten et al 2000). SAP97 interacts with the AMPA receptor subunit GluR1 and stabilizes receptor protein expression at postsynaptic sites (Leonard et al 1998;Jourdi et al 2001;Sans et al 2001).…”

Section: Discussionmentioning

confidence: 99%

Selective reduction of a PDZ protein, SAP‐97, in the prefrontal cortex of patients with chronic schizophrenia

Toyooka

Iritani

Makifuchi

et al. 2002

Journal of Neurochemistry

110

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Many postsynaptic density proteins carrying postsynaptic density-95/discs large/zone occludens-1 (PDZ) domain(s) interact with glutamate receptors to control receptor dynamics and synaptic plasticity. Here we examined the expression of PDZ proteins, synapse-associated protein (SAP) 97, postsynaptic density (PSD)-95, chapsyn-110, GRIP1 and SAP102, in post-mortem brains of schizophrenic patients and control subjects, and evaluated their contribution to schizophrenic pathology. Among these PDZ proteins, SAP97 exhibited the most marked change: SAP97 protein levels were decreased to less than half that of the control levels specifically in the prefrontal cortex of schizophrenic patients. In parallel, its binding partner, GluR1, similarly decreased in the same brain region. The correlation between SAP97 and GluR1 levels in control subjects was, however, altered in schizophrenic patients. SAP102 levels were also significantly reduced in the hippocampus of schizophrenic patients, but this reduction was correlated with sample storage time and post-mortem interval. There were no changes in the levels of the other PDZ proteins in any of the regions examined. In addition, neuroleptic treatment failed to mimic the SAP97 change. These findings suggest that a phenotypic loss of SAP97 is associated with the postsynaptic impairment in prefrontal excitatory circuits of schizophrenic patients. Keywords: chapsyn-110, GRIP1, PSD-95, psychosis, SAP102, SAP97. Address correspondence and reprint requests to Hiroyuki Nawa, Department of Molecular Biology, Brain Research Institute, Niigata University, Asahimachi-dori 1-757, Niigata 951-8585, Japan. E-mail: hnawa@bri.niigata-u.ac.jpAbbreviations used: ABP, AMPA receptor-binding protein; AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid; BDNF, brainderived neurotrophic factor; DTT, dithiothreitol; LPT, long-term potentiation; NSE, neuron-specific enolase; PAGE, polyacrylamide gel electrophoresis; PDZ, PSD-95/discs large/zone occludens-1; PVDF, polyvinylidene difluoride; PSD, postsynaptic density; SAP, synapseassociated protein; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis.

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Section: Discussionmentioning

confidence: 99%

Selective reduction of a PDZ protein, SAP‐97, in the prefrontal cortex of patients with chronic schizophrenia

Toyooka

Iritani

Makifuchi

et al. 2002

Journal of Neurochemistry

110

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“…Phosphorylation of GluR2 subunit at serine-880 has been implicated in LTD both in hippocampus and in cerebellum (Daw et al, 2000, Matsuda et al, 2000, Kim et al, 2001, Chung et al, 2003. Phosphorylation of this site can regulate synaptic localization of AMPA receptors by altering its interaction with intracellular binding partners: Glutamate receptor interacting protein (GRIP)/AMPA receptor binding protein (ABP) and Protein interacting with C-kinase-1 (PICK-1) (Matsuda et al, 1999.…”

Section: Nih Public Accessmentioning

confidence: 99%

Identification and characterization of a novel phosphorylation site on the GluR1 subunit of AMPA receptors

Lee

Takamiya

Kameyama³

et al. 2007

Molecular and Cellular Neuroscience

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Phosphorylation of various AMPA receptor subunits can alter synaptic transmission and plasticity at excitatory glutamatergic synapses in the central nervous system. Here, we identified threonine-840 (T840) on the GluR1 subunit of AMPA receptors as a novel phosphorylation site. T840 is phosphorylated by protein kinase C (PKC) in vitro, and is a highly turned-over phosphorylation site in the hippocampus. Interestingly, the high basal phosphorylation of T840 in the hippocampus is maintained by a persistent activity of a protein kinase, which is counter-balanced by a basal protein phosphatase activity. To study the function of T840, we generated a line of mutant mice lacking this phosphorylation site using a gene knock-in technique. The mice generated lacks T840, in addition to two previously identified phosphorylation sites S831 and S845. Using this mouse, we demonstrate that T840 may regulate synaptic plasticity in an age-dependent manner.Many of the brain functions critically depend on plasticity of the glutamatergic excitatory synaptic transmission, which can be accomplished postsynaptically by modulation of glutamate receptors. AMPA-type glutamate receptors mediate the majority of fast excitatory synaptic transmission, and functional changes to these receptors are implicated in synaptic plasticity (Song and Huganir, 2002, Collingridge et al., 2004). One way to alter the function of AMPA receptors is by changing phosphorylation of its subunits. All four subunits of AMPA receptors, GluR1-4, which have several identified phosphorylation sites on their intracellular carboxy-terminus (Song and Huganir, 2002).Among the four subunits, GluR1 has three identified phosphorylation sites, serines 818 (S818) (Boehm et al., 2006), 831 (S831) and 845 (S845) (Roche et al., 1996). S831 is phosphorylated by calcium/calmodulin-dependent protein kinase II (CaMKII) and protein kinase C (PKC), S845 is a cAMP-dependent protein kinase (PKA) substrate (Roche et al., 1996, Barria et al., 1997a, Mammen et al., 1997, while S818 is phosphorylated by PKC (Boehm et al., 2006). Changes in phosphorylation of GluR1 at S845 and S831 affect AMPA receptor mediated currents (Derkach et al., 1999, Banke et al., 2000, and are involved in long-term potentiation (LTP) and long-term depression (LTD) in the hippocampus (Barria et al., 1997b, Kameyama Correspondence to: Hey-Kyoung Lee. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. , Lee et al., 2003. Recent data suggests that S845 and S818 affect the trafficking AMPA receptors to synapses and/or stabilize synaptic AMPA receptors (Esteban et al., 2003,...

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“…Removal of the PDZ binding site from GluR2 reduces the accumulation of AMPAR levels at the synapse 42 . Moreover, disruption of the interaction between GluR2 and GluR3 and PDZ domains has been reported to block LTD in the hippocampus 43 and cerebellum 44 . These effects appear to be regulated by protein kinase C (PKC), which reduces binding of GluR2 to GRIP and ABP, but not PICK1, by phosphorylating AMPARs at a serine residue (Ser-880) near the C-terminal 45 .…”

Section: When Do Ampars Take a Break?mentioning

confidence: 99%

“…These effects appear to be regulated by protein kinase C (PKC), which reduces binding of GluR2 to GRIP and ABP, but not PICK1, by phosphorylating AMPARs at a serine residue (Ser-880) near the C-terminal 45 . However, disruptions of the interaction between AMPARs and PDZ domains have little consistent effect on baseline synaptic transmission 43 . Moreover, the GluR2-PICK1 interaction appears to be required for cerebellar LTD (Ref.…”

Section: When Do Ampars Take a Break?mentioning

confidence: 99%

“…Moreover, the GluR2-PICK1 interaction appears to be required for cerebellar LTD (Ref. 44 ), but hippocampal LTD requires the GluR2-GRIP/ABP interaction 43 . Given these complexities, a comprehensive model seems far off; nevertheless, the evidence is strong for regulation of AMPAR localization by specific protein-protein interactions at the PDZ binding site.…”

Section: When Do Ampars Take a Break?mentioning

confidence: 99%

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Restless AMPA receptors: implications for synaptic transmission and plasticity

Lüscher

Frerking

2001

Trends in Neurosciences

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A central assumption in neurobiology holds that changes in the strength of individual synapses underlie changes in behavior. This concept is widely accepted in the case of learning and memory where LTP and LTD are the most compelling cellular models. It is therefore of great interest to understand, on a molecular level, how the brain regulates the strength of neuronal connections. We review a large body of evidence in support of the very straightforward regulation of synaptic strength by changing the number of postsynaptic receptors, and discuss the molecular machinery required for insertion and removal of AMPA receptors.The hypothesis that insertion of AMPA receptors (AMPARs) underlies the increase of synaptic strength associated with LTP was put forward almost 20 years ago 1 , but was largely ignored until the mid-1990s, resurfacing with quantal analysis of LTP (Ref. 2 ). However, only recently has it become the subject of direct experimental scrutiny.The spark for the myriad of research published in the past few years in the field was experiments conducted independently by two groups 3,4 , in which single connections between CA3 axons and CA1 pyramidal cells in acute hippocampal slices were functionally isolated and in some cases yielded only responses from NMDA receptors (NMDARs) and not AMPARs. Inducing LTP, however, caused the appearance of AMPAR mediated excitatory postsynaptic currents (EPSCs). This led to the proposal that a fraction of 'silent' synapses contain only NMDARs, and thus are functionally inactive at normal resting potential, but maintain the capability to undergo LTP, which would be expressed by AMPAR insertion. Although alternative explanations for these results have been proposed 5,6 , synapses with NMDARs but not AMPARs have now been directly identified anatomically in cultured hippocampal neurons using immunofluorescence 7,8 and with immuno-gold preparations visualized by electron microscopy in hippocampal slices 9-11 .AMPARs move from the cytoplasm to the surface and back again Constitutive recyclingIf LTP expression is caused by postsynaptic AMPAR insertion, it must be the case that AMPARs can be inserted into and removed from the postsynaptic membrane on a relatively rapid time scale. To test this experimentally, CA1 pyramidal cells in acute hippocampal slices * Christian.Luscher@medecine.unige.ch.

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PDZ Proteins Interacting with C-Terminal GluR2/3 Are Involved in a PKC-Dependent Regulation of AMPA Receptors at Hippocampal Synapses

Cited by 300 publications

References 75 publications

Selective reduction of a PDZ protein, SAP‐97, in the prefrontal cortex of patients with chronic schizophrenia

Selective reduction of a PDZ protein, SAP‐97, in the prefrontal cortex of patients with chronic schizophrenia

Identification and characterization of a novel phosphorylation site on the GluR1 subunit of AMPA receptors

Restless AMPA receptors: implications for synaptic transmission and plasticity

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