SUMOylation and phosphorylation of GluK2 regulate kainate receptor trafficking and synaptic plasticity

Chamberlain, Sophie E.L.; González‐González, Inmaculada M.; Wilkinson, Kevin A.; Konopacki, Filip A.; Kantamneni, Sriharsha; Henley, Jeremy M.; Mellor, Jack R.

doi:10.1038/nn.3089

Cited by 94 publications

(119 citation statements)

References 33 publications

(54 reference statements)

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“…The authors suggested that PKC interacts with PICK1, resulting in disruption of the SNAP-25-PICK1-GluK5 complex. Additional studies also suggest regulation of surface expression of GluK2 by its PKC phosphorylation, although by analogy to our study, the phosphorylation site identification is inconclusive, because mutagenesis of the putative serines to all three relevant residues (Ala, Asp, and Glu) was not done (Nasu-Nishimura et al, 2010, Konopacki et al, 2011, Chamberlain et al, 2012. (B) truncation of the GluK5 C terminus at 837, but not 884, blocked ACPD-induced potentiation of GluK2/GluK5 when coexpressed with mGlu1 (n $ 4).…”

Section: Discussionsupporting

confidence: 54%

“…Cho et al (2003) reported that activation of a G q -coupled group I metabotropic glutamate receptor (likely mGlu5) potentiates GluK1-mediated KAR responses in neurons from the perirhinal cortex in a PKC-dependent manner. Of interest, PKC phosphorylates the C terminus of GluK1 and GluK2 in vitro, which has been proposed to increase the contribution of KARs to the synaptic response , Nasu-Nishimura et al, 2010, Konopacki et al, 2011, Chamberlain et al, 2012. GluK2 is also phosphorylated by the cAMP-dependent protein kinase A (Raymond et al, 1993, Wang et al, 1993, Raymond et al, 1994, Traynelis and Wahl, 1997, Kornreich et al, 2007.…”

Section: Introductionmentioning

confidence: 99%

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Activation of Group I Metabotropic Glutamate Receptors Potentiates Heteromeric Kainate Receptors

et al. 2012

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Kainate receptors (KARs), a family of ionotropic glutamate receptors, are widely expressed in the central nervous system and are critically involved in synaptic transmission. KAR activation is influenced by metabotropic glutamate receptor (mGlu) signaling, but the underlying mechanisms are not understood. We undertook studies to examine how mGlu modulation affects activation of KARs. Confocal immunohistochemistry of rat hippocampus and cultured rat cortex revealed colocalization of the high-affinity KAR subunits with group I mGlu receptors. In hippocampal and cortical cultures, the calcium signal caused by activation of native KARs was potentiated by activation of group I mGlu receptors. In Xenopus laevis oocytes, activation of group I mGlu receptors potentiated heteromeric but not homomeric KAR-mediated currents, with no change in agonist potency. The potentiation of heteromeric KARs by mGlu1 activation was attenuated by GDPbS, blocked by an inhibitor of phospholipase C or the calcium chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N9,N9-tetraacetic acid (BAPTA), prolonged by the phosphatase inhibitor okadaic acid, but unaffected by the tyrosine kinase inhibitor lavendustin A. Protein kinase C (PKC) inhibition reduced the potentiation by mGlu1 of GluK2/GluK5, and conversely, direct activation of PKC by phorbol 12-myristate,13-acetate potentiated GluK2/GluK5. Using site-directed mutagenesis, we identified three serines (Ser833, Ser836, and Ser840) within the membrane proximal region of the GluK5 C-terminal domain that, in combination, are required for mGlu1-mediated potentiation of KARs. Together, these data suggest that phosphorylation of key residues in the C-terminal domain changes the overall charge of this domain, resulting in potentiated agonist responses.

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Section: Discussionsupporting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Activation of Group I Metabotropic Glutamate Receptors Potentiates Heteromeric Kainate Receptors

et al. 2012

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“…A sequence scan of the C terminus of KAR subunits reveals a number of consensus phosphorylation sites for the protein kinases PKC, PKA, CaMKII, and Src. PKC phosphorylates the C terminus of both GluK1 and GluK2 in vitro Nasu-Nishimura et al, 2010;Konopacki et al, 2011;Chamberlain et al, 2012). The phosphorylation of GluK2 by PKC at Ser868 is a critical step in the process of internalization of GluK2 that occurs during KAR-mediated LTP in hippocampal mossy fibers (Chamberlain et al, 2012).…”

Section: Kainate Receptorsmentioning

confidence: 99%

“…PKC phosphorylates the C terminus of both GluK1 and GluK2 in vitro Nasu-Nishimura et al, 2010;Konopacki et al, 2011;Chamberlain et al, 2012). The phosphorylation of GluK2 by PKC at Ser868 is a critical step in the process of internalization of GluK2 that occurs during KAR-mediated LTP in hippocampal mossy fibers (Chamberlain et al, 2012). On the other hand phosphorylation of Cterminal residues (i.e., Ser880 and Ser886) in GluK1 appears to promote the stability of this subunit in the synapse via an interaction with the PDZ domain containing protein GRIP1 .…”

Section: Kainate Receptorsmentioning

confidence: 99%

Ionotropic Glutamate Receptors: Regulation by G-Protein-Coupled Receptors

Rojas

Dingledine

2013

Mol Pharmacol

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The function of many ion channels is under dynamic control by coincident activation of G-protein-coupled receptors (GPCRs), particularly those coupled to the G as and G aq family members. Such regulation is typically dependent on the subunit composition of the ionotropic receptor or channel as well as the GPCR subtype and the cell-specific panoply of signaling pathways available. Because GPCRs and ion channels are so highly represented among targets of U.S. Food and Drug Administration-approved drugs, functional cross-talk between these drug target classes is likely to underlie many therapeutic and adverse effects of marketed drugs. GPCRs engage a myriad of signaling pathways that involve protein kinases A and C (PKC) and, through PKC and interaction with b-arrestin, Src kinase, and hence the mitogen-activated-protein-kinase cascades. We focus here on the control of ionotropic glutamate receptor function by GPCR signaling because this form of regulation can influence the strength of synaptic plasticity. The amino acid residues phosphorylated by specific kinases have been securely identified in many ionotropic glutamate (iGlu) receptor subunits, but which of these sites are GPCR targets is less well known even when the kinase has been identified. N-methyl-D-aspartate, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and heteromeric kainate receptors are all downstream targets of GPCR signaling pathways. The details of GPCR-iGlu receptor cross-talk should inform a better understanding of how synaptic transmission is regulated and lead to new therapeutic strategies for neuropsychiatric disorders.

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“…Sumoylation of the transcription factor MeCP2 also leads to transcriptional repression, known to play a role in synaptic development (128). Directional transport of proteins in axons has also been shown to be SUMO dependent (129); and sumoylation and phosphorylation have further shown to have synergistic effects (130).…”

Section: Importance Of Proteomics In Identifying Mechanismsmentioning

confidence: 99%

Molecular and Cellular Mechanisms of Axonal Regeneration After Spinal Cord Injury

Niekerk

Tuszynski

et al. 2016

Molecular & Cellular Proteomics

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Following axotomy, a complex temporal and spatial coordination of molecular events enables regeneration of the peripheral nerve. In contrast, multiple intrinsic and extrinsic factors contribute to the general failure of axonal regeneration in the central nervous system. In this review, we examine the current understanding of differences in protein expression and post-translational modifications, activation of signaling networks, and environmental cues that may underlie the divergent regenerative capacity of central and peripheral axons. We also highlight key experimental strategies to enhance axonal regeneration via modulation of intraneuronal signaling networks and the extracellular milieu. Finally, we explore potential applications of proteomics to fill gaps in the current understanding of molecular mechanisms underlying regeneration, and to provide insight into the development of more effective approaches to promote axonal regeneration following injury to the nervous system. Molecular & Cellular Proteomics

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SUMOylation and phosphorylation of GluK2 regulate kainate receptor trafficking and synaptic plasticity

Cited by 94 publications

References 33 publications

Activation of Group I Metabotropic Glutamate Receptors Potentiates Heteromeric Kainate Receptors

Activation of Group I Metabotropic Glutamate Receptors Potentiates Heteromeric Kainate Receptors

Ionotropic Glutamate Receptors: Regulation by G-Protein-Coupled Receptors

Molecular and Cellular Mechanisms of Axonal Regeneration After Spinal Cord Injury

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