Details of a Researcher - Nuriya, Mutsuo

Papers - Nuriya, Mutsuo

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Regulation of AMPA receptor trafficking by N-cadherin

Nuriya Mutsuo, Huganir Richard L.

Journal of Neurochemistry 97 ( 3 ) 652 - 661 2006.05

ISSN 0022-3042

Dendritic spines are dynamically regulated, both morphologically and functionally, by neuronal activity. Morphological changes are mediated by a variety of synaptic proteins, whereas functional changes can be dramatically modulated by the regulation of α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor trafficking. Although these two forms of plasticity appear to be highly coordinated, the connections between them are not fully understood. In this study the synaptic cell adhesion molecule N-cadherin was found to associate with AMPA receptors and regulate AMPA receptor trafficking in neurons. N-cadherin and β-catenin formed a protein complex with AMPA receptors in vivo, and this association was regulated by extracellular Ca²⁺. In addition, these proteins co-clustered at synapses in cultured neurons. In heterologous cells and in cultured neurons, overexpression of wild-type N-cadherin specifically increased the surface expression level of the AMPA receptor subunit glutamate receptor 1 (GluR1)q4 and this effect was reversed by a dominant-negative form of N-cadherin. Finally, GluR1 increased the surface expression of N-cadherin in heterologous cells. Importantly, recent studies suggest that N-cadherin and β-catenin play key roles in structural plasticity in neurons. Therefore, our data suggest that the association of N-cadherin with AMPA receptors may serve as a biochemical link between structural and functional plasticity of synapses. © 2006 International Society for Neurochemistry.

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Imaging membrane potential in dendritic spines

Nuriya Mutsuo, Jiang Jiang, Nemet Boaz, Eisenthal Kenneth B., Yuste Rafael

Proceedings of the National Academy of Sciences of the United States of America 103 ( 3 ) 786 - 790 2006.01

ISSN 0027-8424

Dendritic spines mediate most excitatory inputs in the brain. Although it is clear that spines compartmentalize calcium, it is still unknown what role, if any, they play in integrating synaptic inputs. To investigate the electrical function of spines directly, we used second harmonic generation (SHG) imaging of membrane potential in pyramidal neurons from hippocampal cultures and neocortical brain slices. With FM 4-64 as an intracellular SHG chromophore, we imaged membrane potential in the soma, dendritic branches, and spines. The SHG response to voltage was linear and seemed based on an electro-optic mechanism. The SHG sensitivity of the chromophore in spines was similar to that of the parent dendritic shaft and the soma. Backpropagation of somatic action potentials generated SHG signals at spines with similar amplitude and kinetics to somatic ones. Our optical measurements of membrane potential from spines demonstrate directly that backpropagating action potentials invade the spines. © 2006 by The National Academy of Sciences of the USA.

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Phosphorylation-dependent interactions of α-Actinin-1/IQGAP1 with the AMPA receptor subunit GluR4

Nuriya Mutsuo, Oh Sekyung, Huganir Richard L.

Journal of Neurochemistry 95 ( 2 ) 544 - 552 2005.10

ISSN 0022-3042

AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors play key roles in excitatory synaptic transmission and synaptic plasticity in the CNS. Although a variety of proteins has been characterized to interact with AMPA receptors and regulate their function, little is known about the regulation of the AMPA receptor subunit GluR4. To understand the molecular mechanisms of GluR4 functional regulation, the yeast two-hybrid system was used to identify GluR4-interacting molecules. α-Actinin-1 and IQGAP1 were identified to be GluR4-specific binding partners. Both proteins interact specifically with GluR4 and co-cluster with GluR4 individually in neurons. Mapping experiments revealed that α-Actinin-1 and IQGAP1 bind to the same region within the C-terminus of GluR4 that contains a previously identified PKA phosphorylation site, Ser842, phosphorylation of which is regulated by synaptic activity. Interestingly, the phosphorylation of Ser842 differentially regulates interactions of GluR4 with α-Actinin-1 and IQGAP1; phosphorylation strongly inhibits interaction of GluR4 with α-Actinin-1 but has little effect on its interaction with IQGAP1. These results suggest that α-Actinin-1 and IQGAP1 regulate GluR4 functions via their specific associations with GluR4. In addition, our data indicate that activity-dependent phosphorylation of GluR4 may regulate its synaptic targeting through phosphorylation-dependent interactions with α-Actinin-1 and IQGAP1. © 2005 International Society for Neurochemistry.

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Metabotropic glutamate and dopamine receptors co-regulate AMPA receptor activity through PKA in cultured chick retinal neurones

Gomes André R., Cunha Paulo, Nuriya Mutsuo, Faro Carlos J., Huganir Richard L., Pires Euclides V., Carvalho Ana Luísa, Duarte Carlos B.

Journal of Neurochemistry 90 ( 3 ) 673 - 682 2004.08

ISSN 0022-3042

Glutamate receptor phosphorylation has been implicated in several forms of modulation of synaptic transmission. It has been reported that protein kinase A (PKA) can phosphorylate the α-amino-3-hydroxy-5-methyl-4- isoxazolepropionate (AMPA) receptor subunit GluR4 on Ser842, both in vitro and in vivo. Here, we studied the regulation of GluR4 phosphorylation and intracellular trafficking by PKA and by metabotropic receptors coupled to adenylyl cyclase (AC), in cultured chick retinal amacrine-like neurones, which are enriched in GluR4. The regulation of AMPA receptor activity by PKA and by metabotropic AC-coupled receptors was also investigated by measuring the [Ca²⁺]_i response to kainate in Na⁺-free medium. Stimulation of AC with forskolin (FSK), or using the selective agonist of dopamine D₁ receptors (±)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3- benzazepine-7,8-diol (SKF38393), increased the [Ca²⁺]_i response to kainate, GluR4 phosphorylation at Ser842 and GluR4 surface expression. Pre-incubation of the cells with (2S,2′R,3′R)-2- (2′,3′-dicarboxycyclopropyl)glycine (DCG-IV), an agonist of group II metabotropic glutamate receptors (mGluR), which are coupled to inhibition of AC, inhibited the effect of FSK and of SKF38393 on AMPA receptor activity, GluR4 phosphorylation and expression at the plasma membrane. These results indicate that there is a functional cross-talk between dopamine D₁ receptors and group II mGluR in the regulation of GluR4 phosphorylation and AMPA receptor activity. Our data show that GluR4 phosphorylation at Ser842 by PKA, and its recruitment to the plasma membrane upon phosphorylation, is regulated by metabotropic receptors.

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PKA phosphorylation of AMPA receptor subunits controls synaptic trafficking underlying plasticity

Esteban José A., Shi Song Hai, Wilson Christopher, Nuriya Mutsuo, Huganir Richard L., Malinow Roberto

Nature Neuroscience 6 ( 2 ) 136 - 143 2003.02

ISSN 1097-6256

The regulated incorporation of AMPA receptors into synapses is important for synaptic plasticity. Here we examine the role of protein kinase A (PKA) in this process. We found that PKA phosphorylation of the AMPA receptor subunits GluR4 and GluR1 directly controlled the synaptic incorporation of AMPA receptors in organotypic slices from rat hippocampus. Activity-driven PKA phosphorylation of GluR4 was necessary and sufficient to relieve a retention interaction and drive receptors into synapses. In contrast, PKA phosphorylation of GluR1 and the activity of calcium/calmodulin-dependent kinase II (CaMKII) were both necessary for receptor incorporation. Thus, PKA phosphorylation of AMPA receptor subunits contributes to diverse mechanisms underlying synaptic plasticity.

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Structure of the Homer EVH1 domain-peptide complex reveals a new twist in polyproline recognition

Beneken Jutta, Tu Jian Cheng, Xiao Bo, Nuriya Mutsuo, Yuan Joseph P., Worley Paul F., Leahy Daniel J.

Neuron 26 ( 1 ) 143 - 154 2000

ISSN 0896-6273

Homer EVH1 (Ena/VASP Homology 1) domains interact with proline-rich motifs in the cytoplasmic regions of group 1 metabotropic glutamate receptors (mGluRs), inositol-1,4,5-trisphosphate receptors (IP3Rs), and Shank proteins. We have determined the crystal structure of the Homer EVH1 domain complexed with a peptide from mGluR (TPPSPF). In contrast to other EVH1 domains, the bound mGluR ligand assumes an unusual conformation in which the side chains of the Ser-Pro tandem are oriented away from the Homer surface, and the Phe forms a unique contact. This unusual binding mode rationalizes conserved features of both Homer and Homer ligands that are not shared by other EVH1 domains. Site-directed mutagenesis confirms the importance of specific Homer residues for ligand binding. These results establish a molecular basis for understanding the biological properties of Homer-ligand complexes.

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