Phosphorylation and Modulation of a Kainate Receptor (GluR6) by cAMP-Dependent Protein Kinase

Wang, Lu-Yang; Taverna, Franco A.; Huang, Xi‐Ping; MacDonald, John F.; Hampson, David R.

doi:10.1126/science.8382377

Cited by 224 publications

(137 citation statements)

References 23 publications

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“…Inconsistent with the conclusion from these topology studies, however, were findings from several groups that residues in the M3-M4 linker of non-NMDA glutamate receptors could be phosphorylated (21)(22)(23)(24)(25). Most notably, two separate laboratories had determined that a serine residue (Ser-684) in the M3-M4 linker of GluR6 acted as a substrate for protein kinase A (PKA) (21,22).…”

mentioning

confidence: 62%

“…Homologous residues appear in boldface type. Putative phosphorylation targets are shown with a black background: Ser-684 in GluR6 (21,22), Ser-696 in GluR2 (25), and the artificial NR1-PKA mutation (this paper). The NR1-PKA mutation (underlined residues and top row) was constructed to encode a canonical PKA site (56 -58) around an existing serine (713) using the following mutation: N710R,Y711R,E712A,A714L …”

Section: Resultsmentioning

confidence: 99%

“…Most notably, two separate laboratories had determined that a serine residue (Ser-684) in the M3-M4 linker of GluR6 acted as a substrate for protein kinase A (PKA) (21,22). The topology studies and the GluR6 phosphorylation data may be reconciled if two short transmembrane regions flanking the phosphorylation site are invoked ( Fig.…”

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confidence: 99%

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An Alanine Residue in the M3-M4 Linker Lines the Glycine Binding Pocket of the N-Methyl-D-aspartate Receptor

Wood¹,

VanDongen

1997

Journal of Biological Chemistry

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While attempting to map a central region in the M3-M4 linker of the N-methyl-D-aspartate receptor NR1 subunit, we found that mutation of a single position, Ala-714, greatly reduced the apparent affinity for glycine. Proximal N-glycosylation localized this region to the extracellular space. Glycine affinities of additional Ala-714 mutations correlated with side chain volume. Substitution of alanine 714 with cysteine did not alter glycine sensitivity, although this mutant was rapidly inhibited by dithionitrobenzoate. Glycine protected the A714C mutant from modification by dithionitrobenzoate, whereas the co-agonist L-glutamate was ineffective. These experiments place Ala-714 in the glycine binding pocket of the N-methyl-D-aspartate receptor, a determination not predicted by previous structural models based on bacterial periplasmic binding protein homology.The N-methyl-D-aspartate (NMDA) 1 receptor is distinguished among the ionotropic glutamate receptors by several properties. The receptor possesses a unique Ca 2ϩ permeability and a voltage-dependent Mg 2ϩ block (1). These two features define the NMDA receptor's role in several important physiologic phenomena, including long term potentiation, neuronal development, and excitotoxicity (2). However, the functional characteristic that may most differentiate the NMDA receptor from other glutamate receptors is a requirement for the coagonist glycine (3, 4). Occupancy of both glutamate and glycine binding sites is necessary for receptor activation, and the two sites are allosterically coupled (5, 6). The distinct glycine binding site has been suggested to play a role in regulation of NMDA receptor desensitization (7). While several residues in the amino terminus of NR1 have been demonstrated to greatly influence glycine affinity, binding is also modulated by the contributing NR2 subunits (8). Indeed, the glycine binding site is a current experimental target for therapeutic intervention in the hours immediately following ischemic stroke (9).Despite functional differences among the glutamate receptors, several recent studies have converged upon a single topology model for the ionotropic glutamate receptor family (10 -14). Speculation of alternate glutamate receptor topology was suggested by several early investigations (15)(16)(17)(18)(19). Several subsequent systematic studies concluded that non-NMDA glutamate receptor subunits possessed a three-transmembrane domain architecture (11,12,20). By generating functional N-linked glycosylation mutants of the NMDA NR1 subunit, we tested the hypothesized existence of a conserved hairpin pore structure similar to that found in voltage-gated K ϩ channels (13), thus supporting the three-transmembrane domain model. An important consequence of the new three-transmembrane domain configuration is an extracellular location of the M3-M4 linker.Inconsistent with the conclusion from these topology studies, however, were findings from several groups that residues in the M3-M4 linker of non-NMDA glutamate receptors could be phosphorylated (2...

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confidence: 62%

Section: Resultsmentioning

confidence: 99%

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An Alanine Residue in the M3-M4 Linker Lines the Glycine Binding Pocket of the N-Methyl-D-aspartate Receptor

Wood¹,

VanDongen

1997

Journal of Biological Chemistry

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“…This interpretation is consistent with previous evidence for both kainate (Bowie and Lang, 2002) and AMPA (Tang et al 1989;Bowie and Lange, 2002) receptors that different open states underlie the initial peak current and the steady-state current recorded at equilibrium. In addition, the independent effects of KRIP6 on peak and steady-state currents may reflect differences among channel populations in the phosphorylation (Raymond et al, 1993;Wang et al, 1993) or palmitoylation (Pickering et al, 1995) state of GluR6. Such post-translational modifications could functionally segregate GluR6 containing kainate receptors into different pools or vary accessibility to functional regulation by KRIP6.…”

Section: Discussionmentioning

confidence: 99%

KRIP6: A novel BTB/kelch protein regulating function of kainate receptors

Laezza

Wilding

Sequeira

et al. 2007

Molecular and Cellular Neuroscience

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Whereas many interacting proteins have been identified for AMPA and NMDA glutamate receptors, fewer are known to directly bind and regulate function of kainate receptors. Using a yeast two-hybrid screen for interacting partners of the C-terminal domain of GluR6a, we identified a novel neuronal protein of the BTB/kelch family, KRIP6. KRIP6 binds to the GluR6a C-terminal domain at a site distinct from the PDZ-binding motif and it co-immunoprecipitates with recombinant and endogenous GluR6. Co-expression of KRIP6 alters GluR6 mediated currents in a heterologous expression system reducing peak current amplitude and steady-state desensitization, without affecting surface levels of GluR6. Endogenous KRIP6 is widely expressed in brain and overexpression of KRIP6 reduces endogenous kainate receptor-mediated responses evoked in hippocampal neurons. Taken together, these results suggest that KRIP6 can directly regulate native kainate receptors and provide the first evidence for a BTB/kelch protein in direct functional regulation of a mammalian glutamate receptor.

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“…For example, PSI2 might act as a kinase that could desensitize phyA and phyB by phosphorylation. Desensitization of receptors by phosphorylation has been described in other signaling systems (Wang et al, 1993;Goodman et al, 1996; Zhang et al, 1997).Light-responsive genes are constitutively (i.e., irrespective of the presence of light) derepressed by cop/det/fus mutations, which also affect the expression of several other gene sets (Mayer et al, 1996). In contrast, the psi2 phenotype is strictly dependent on red or far-red light.…”

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confidence: 98%

An Arabidopsis Mutant Hypersensitive to Red and Far-Red Light Signals

et al. 1998

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A new mutant called psi2 (for p hytochrome si gnaling) was isolated by screening for elevated activity of a chlorophyll a / b binding protein-luciferase ( CAB2-LUC ) transgene in Arabidopsis. This mutant exhibited hypersensitive induction of CAB1 , CAB2 , and the small subunit of ribulose-1,5-bisphosphate carboxylase ( RBCS ) promoters in the very low fluence range of red light and a hypersensitive response in hypocotyl growth in continuous red light of higher fluences. In addition, at high-but not low-light fluence rates, the mutant showed light-dependent superinduction of the pathogenrelated protein gene PR-1a and developed spontaneous necrotic lesions in the absence of any pathogen. Expression of genes responding to various hormone and environmental stress pathways in the mutant was not significantly different from that of the wild type. Analysis of double mutants demonstrated that the effects of the psi2 mutation are dependent on both phytochromes phyA and phyB. The mutation is recessive and maps to the bottom of chromosome 5. Together, our results suggest that PSI2 specifically and negatively regulates both phyA and phyB phototransduction pathways. The induction of cell death by deregulated signaling pathways observed in psi2 is reminiscent of retinal degenerative diseases in animals and humans. INTRODUCTIONBecause light provides the energy source for photosynthesis, plants must adapt to changes in ambient light quantity and quality to optimize the efficiency of this important process. The results of this adaptation are apparent: almost every step of plant development, from seed germination to fruit maturation, is dependent on light. Moreover, light regulates the circadian rhythm, the adaptative size modification of tissue and organs, and the expression of photosynthetic genes and many other known and unknown genes (Terzaghi and Cashmore, 1995).To date, what we know about light information processing and signal transduction concerns the nature and function of photoreceptors. A family of photoreceptors called phytochromes has been shown to be involved in the perception of red and far-red light. Their biochemical and molecular properties and physiological roles are now well described (reviewed in Quail et al., 1995;Smith, 1995). In addition, a longpostulated UV and blue light receptor (cryptochrome) was recently characterized by Ahmad and Cashmore (1993). Mutants lacking one or several of these receptors have provided useful information concerning the role of individual photoreceptors and their interaction in transducing light signals (reviewed in Barnes et al., 1997).Much less is known concerning molecules that link light perception to gene activation. The CONSTITUTIVE PHOTO-MORPHOGENIC/DEETIOLATED/FUSCA (COP/DET/FUS) class of proteins has been suggested to play an important role in regulating the repression of light-inducible genes and the maintenance of skotomorphogenesis (Chory et al., 1989). For some of these proteins, the genes have been cloned and include COP1 (Deng et al., 1992), DET1 (Pepper et al., ...

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Phosphorylation and Modulation of a Kainate Receptor (GluR6) by cAMP-Dependent Protein Kinase

Cited by 224 publications

References 23 publications

An Alanine Residue in the M3-M4 Linker Lines the Glycine Binding Pocket of the N-Methyl-D-aspartate Receptor

An Alanine Residue in the M3-M4 Linker Lines the Glycine Binding Pocket of the N-Methyl-D-aspartate Receptor

KRIP6: A novel BTB/kelch protein regulating function of kainate receptors

An Arabidopsis Mutant Hypersensitive to Red and Far-Red Light Signals

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