Details of a Researcher - Nuriya, Mutsuo

Papers - Nuriya, Mutsuo

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Norepinephrine induces rapid and long-lasting phosphorylation and redistribution of connexin 43 in cortical astrocytes

Nuriya, Mutsuo, Morita, Ayaka, Shinotsuka, Takanori, Yamada, Tomoko, Yasui, Masato

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS (Biochemical and Biophysical Research Communications) 504 ( 4 ) 690 - 697 2018.10

Research paper (scientific journal), ISSN 0006-291X

© 2018 Elsevier Inc. Norepinephrine (NE) modulates brain functions depending on both the internal and external environment. While the neuromodulatory actions of NE have been well characterized, the response and involvement of cortical astrocytes to physiological noradrenergic systems remain largely unknown, especially at the molecular level. In this study, we biochemically characterize the action of NE on astrocytes of the murine neocortex. NE stimulation of acute brain slices rapidly increase phosphorylation of connexin 43 (Cx43) at Serine (Ser) 368, in slices from both juvenile and adolescent animals. The phosphorylation is mediated by the protein kinase C (PKC) pathway under the α1-adrenergic receptor and remains elevated for tens of minutes following brief exposure to NE, well after the intracellular calcium level returns to normal level, suggesting the plastic nature of this phosphorylation event. Importantly, this phosphorylation event persists in the absence of neuronal transmissions, suggesting that the effect of NE on Cx43 phosphorylation is induced directly on astrocytes. Furthermore, these NE-induced phosphorylations are associated with biochemical dissociation of Cx43 from gap-junctional plaques to non-junctional compartments. Finally, we show that pharmacological manipulation of the noradrenergic system using psychoactive drugs modulates phosphorylation of Cx43 in the cerebral cortex in vivo. These data suggest that NE acts directly on astrocytes in parallel with neurons and modulates functionally critical connexin channel proteins in a plastic manner. Thus, plasticity of astrocytes induced by the “gliomodulatory” actions of NE may play important roles in their physiological as well as pharmacological actions in the brain.

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Direct posttranslational modification of astrocytic connexin 43 proteins by the general anesthetic propofol in the cerebral cortex

Nuriya, Mutsuo, Yasui, Daisuke, Yamada, Tomoko, Aoki, Takuma, Yasui, Masato

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS (Biochemical and Biophysical Research Communications) 497 ( 2 ) 734 - 741 2018.03

Research paper (scientific journal), ISSN 0006-291X

© 2018 Elsevier Inc. Propofol is widely used as a general anesthetic and is generally considered to exert its action by regulating neuronal firing via facilitation of GABAA receptors. However, accumulating evidence suggests that propofol also acts on astrocytes, including inhibitory effects on gap junctional coupling, but the underlying molecular mechanisms remain largely unknown. Here, using acute cortical brain slices prepared from mice, we characterize propofol-induced molecular changes in astrocytic gap junction protein connexin 43 (Cx43). Propofol does not change the protein expression level of Cx43 or its incorporation into gap junctional plaques, according to biochemical and immunohistochemical analyses. However, propofol alters migration pattern of Cx43 on western blot, suggesting changes in its posttranslational modifications. Indeed, this change is accompanied by an increase in the phosphorylation of Cx43 at serine 368, which is known to reduce permeability of Cx43 gap junctions. Finally, we show that this change occurs in the absence of neuronal firing or glutamatergic transmissions. Overall, these results show that propofol induces posttranslational modification of Cx43 directly on astrocytes at the site of gap junctional plaques, exerting direct pharmacological action on astrocytes in parallel with its action on neurons.

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Background norepinephrine primes astrocytic calcium responses to subsequent norepinephrine stimuli in the cerebral cortex

Nuriya, Mutsuo, Takeuchi, Miyabi, Yasui, Masato

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 483 ( 1 ) 732 - 738 2017.01

Research paper (scientific journal), ISSN 0006-291X

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Multimodal two-photon imaging using a second harmonic generation-specific dye

Nuriya, Mutsuo, Fukushima, Shun, Momotake, Atsuya, Shinotsuka, Takanori, Yasui, Masato, Arai, Tatsuo

NATURE COMMUNICATIONS 7 732 - 738 2016.05

Research paper (scientific journal), ISSN 2041-1723

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Astrovascular interaction

Nuriya Mutsuo

Folia Pharmacologica Japonica 145 ( 6 ) 326 - 328 2015.06

ISSN 0015-5691

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Sustained down-regulation of β-dystroglycan and associated dysfunctions of astrocytic endfeet in epileptic cerebral cortex

Gondo Asako, Shinotsuka Takanori, Morita Ayaka, Abe Yoichiro, Yasui Masato, Nuriya Mutsuo

Journal of Biological Chemistry 289 ( 44 ) 30279 - 30288 2014.10

ISSN 0021-9258

Epilepsy is characterized by the abnormal activation of neurons in the cerebral cortex, but the molecular and cellular mechanisms contributing to the development of recurrent seizures are largely unknown. Recently, the critical involvement of astrocytes in the pathophysiology of epilepsy has been proposed. However, the nature of plastic modulations of astrocytic proteins in the epileptic cortex remains poorly understood. In this study, we utilized the zero magnesium in vitro model of epilepsy and examined the potential molecular changes of cortical astrocytes, focusing specifically on endfeet, where specialized biochemical compartments exist. We find that the continuous epileptic activation of neurons for 1 h decreases the expression level of β-dystroglycan (βDG) in acute cortical brain slices prepared from mice. This change is completely abolished by the pharmacological blockade of NMDA-type glutamate receptors as well as by matrix metalloproteinase inhibitors. Consistent with the highly specialized localization of βDG at astrocytic endfeet, where it plays a pivotal role in anchoring endfeet-enriched proteins in astrocytes, the down-regulation of βDG is accompanied by a decrease in the expression of AQP4 but not laminin. Importantly, this down-regulation of βDG persists for at least 1 h, even after the apparent recovery of neuronal activation. Finally, we show that the down-regulation of βDG is associated with the dysfunction of the endfeet at the blood-brain interface as a diffusion barrier. These results suggest that the sustained downregulation of βDG leads to dysfunctions of astrocytic endfeet in the epileptic cerebral cortex and may contribute to the pathogenesis of epilepsy.

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Astrocytic gap junctional networks suppress cellular damage in an in vitro model of ischemia

Shinotsuka Takanori, Yasui Masato, Nuriya Mutsuo

Biochemical and Biophysical Research Communications 444 ( 2 ) 171 - 176 2014.02

ISSN 0006-291X

Astrocytes play pivotal roles in both the physiology and the pathophysiology of the brain. They communicate with each other via extracellular messengers as well as through gap junctions, which may exacerbate or protect against pathological processes in the brain. However, their roles during the acute phase of ischemia and the underlying cellular mechanisms remain largely unknown. To address this issue, we imaged changes in the intracellular calcium concentration ([Ca²⁺]_i) in astrocytes in mouse cortical slices under oxygen/glucose deprivation (OGD) condition using two-photon microscopy. Under OGD, astrocytes showed [Ca²⁺]_i oscillations followed by larger and sustained [Ca²⁺]_i increases. While the pharmacological blockades of astrocytic receptors for glutamate and ATP had no effect, the inhibitions of gap junctional intercellular coupling between astrocytes significantly advanced the onset of the sustained [Ca²⁺]_i increase after OGD exposure. Interestingly, the simultaneous recording of the neuronal membrane potential revealed that the onset of the sustained [Ca²⁺]_i increase in astrocytes was synchronized with the appearance of neuronal anoxic depolarization. Furthermore, the blockade of gap junctional coupling resulted in a concurrent faster appearance of neuronal depolarizations, which remain synchronized with the sustained [Ca²⁺]_i increase in astrocytes. These results indicate that astrocytes delay the appearance of the pathological responses of astrocytes and neurons through their gap junction-mediated intercellular network under OGD. Thus, astrocytic gap junctional networks provide protection against tissue damage during the acute phase of ischemia. © 2014 Elsevier Inc. All rights reserved.

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Diffusion properties of molecules at the blood-brain interface

Nuriya Mutsuo, Shinotsuka Takanori, Yasui Masato

Cerebral Cortex 23 ( 9 ) 2118 - 2126 2013.09

ISSN 1047-3211

Molecular diffusion in the extracellular space (ECS) plays a key role in determining tissue physiology and pharmacology. The blood-brain barrier regulates the exchange of substances between the brain and the blood, but the diffusion properties of molecules at this blood-brain interface, particularly around the astrocyte endfeet, are poorly characterized. In this study, we used 2-photon microscopy and acute brain slices of mouse neocortex and directly assessed the diffusion patterns of fluorescent molecules. By observing the diffusion of unconjugated and 10-kDa dextran-conjugated Alexa Fluor 488 from the ECS of the brain parenchyma to the blood vessels, we find various degrees of diffusion barriers at the endfeet: Some allow the invasion of dye inside the endfoot network while others completely block it. Detailed analyses of the time course for dye clearance support the existence of a tight endfoot network capable of acting as a diffusion barrier. Finally, we show that this diffusion pattern collapses under pathological conditions. These data demonstrate the heterogeneous nature of molecular diffusion dynamics around the endfeet and suggest that these structures can serve as the diffusion barrier. Therefore, astrocyte endfeet may add another layer of regulation to the exchange of molecules between blood vessels and brain parenchyma. © 2012 The Author.

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Endfeet serve as diffusion-limited subcellular compartments in astrocytes

Nuriya Mutsuo, Yasui Masato

Journal of Neuroscience 33 ( 8 ) 3692 - 3698 2013.02

ISSN 0270-6474

Astrocytes extend their processes to make contact with neurons and blood vessels and regulate important processes associated with the physiology/pathophysiology of the brain. Their elaborate morphology, with numerous fine processes, could allow them to perform complex signal transductions with distinct compartments or to function as a spatial buffer depending on the diffusion properties of their intracellular molecules. Apart from calcium ions, however, the diffusion dynamics of molecules within astrocytes are poorly understood. In this study, we applied two-photon uncaging and fluorescence recovery after photobleaching of fluorescent molecules to acute cortical brain slices from mice to investigate the diffusion dynamics of molecules within astrocytes. We found that diffusion was significantly more restricted at the endfeet than at trunks and distal ends of other processes. Slow diffusion dynamics at the endfeet resulted in a large population of molecules being retained in a small region for tens of seconds, creating subcellular compartments that were isolated from other regions. In contrast, diffusion was fast and free at other processes. The same patterns were observed with the diffusions of a higher molecular weight (10 kDa) molecule and 2-NBDG, a fluorescent analog of glucose. These findings suggest that molecular diffusion is not uniform across the intracellular environment and that subcellular compartments are present in astrocytes. Therefore, similar to neurons, the elaborate and specialized structures of astrocytes may enable them to perform complex computations by providing distinct information storage/processing capacity among processes. © 2013 the authors.

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Evaluation of dialkylaminofluorene-based hemicyanine dyes for second harmonic generation imaging by the direct comparison approach

Nuriya Mutsuo, Momotake Atsuya, Kimura Yuta, Yasui Masato, Kasai Haruo, Arai Tatsuo

Bulletin of the Chemical Society of Japan 86 ( 10 ) 1190 - 1192 2013

ISSN 0009-2673

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A phosphatidylinositol lipids system, lamellipodin, and Ena/VASP regulate dynamic morphology of multipolar migrating cells in the developing cerebral cortex

Yoshinaga Satoshi, Ohkubo Takahiro, Sasaki Shinji, Nuriya Mutsuo, Ogawa Yukino, Yasui Masato, Tabata Hidenori, Nakajima Kazunori

Journal of Neuroscience 32 ( 34 ) 11643 - 11656 2012.08

ISSN 0270-6474

In the developing mammalian cerebral cortex, excitatory neurons are generated in the ventricular zone (VZ) and subventricular zone; these neurons migrate toward the pial surface. The neurons generated in theVZassume a multipolar morphology and remain in a narrow region called the multipolar cell accumulation zone (MAZ) for~24 h, in which they extend and retract multiple processes dynamically. They eventually extend an axon tangentially and begin radial migration using a migratory mode called locomotion. Despite the potential biological importance of the process movement of multipolar cells, the molecular mechanisms remain to be elucidated. Here, we observed that the processes of mouse multipolar cells were actin rich and morphologically resembled the filopodia and lamellipodia in growth cones; thus, we focused on the actin-remodeling proteins Lamellipodin (Lpd) and Ena/vasodilator-stimulated phosphoprotein (VASP). Lpd binds to phosphatidylinositol (3,4)-bisphosphate [PI(3,4)P₂] and recruits Ena/VASP, which promotes the assembly of actin filaments, to the plasma membranes. In situ hybridization and immunohistochemistry revealed that Lpd is expressed in multipolar cells in the MAZ. The functional silencing of either Lpd or Ena/VASP decreased the number of primary processes. Immunostaining and a Förster resonance energy transfer analysis revealed the subcellular localization of PI(3,4)P₂ at the tips of the processes. A knockdown experiment and treatment with an inhibitor for Src homology 2-containing inositol phosphatase-2, a 5-phosphatase that produces PI(3,4)P₂ from phosphatidylinositol (3,4,5)-triphosphate, decreased the number of primary processes. Our observations suggest that PI(3,4)P₂, Lpd, and Ena/VASP are involved in the process movement of multipolar migrating cells. ©2012 the authors.

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Proteomic analysis of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor complexes

Kang Myoung Goo, Nuriya Mutsuo, Guo Yurong, Martindale Kevin D., Lee Daniel Z., Huganir Richard L.

Journal of Biological Chemistry 287 ( 34 ) 28632 - 28645 2012.08

ISSN 0021-9258

The AMPA receptor (AMPA-R) is a major excitatory neurotransmitter receptor in the brain. Identifying and characterizing the neuronal proteins interacting with AMPA-Rs have provided important information about the molecular mechanisms underlying synaptic transmission and plasticity. In this study, to identify more AMPA-R interactors in vivo, we performed proteomic analyses of AMPA-R complexes from the brain.AMPA-Rcomplexes were isolated from the brain through various combinations of biochemical techniques for solubilization, enrichment, and immunoprecipitation. Mass spectrometry analyses of these isolated complexes identified several novel components of the AMPA-R complexes as well as some previously identified components. The identification of these novel components helps to further define the complex mechanisms involved in the regulation of AMPA receptor function and synaptic plasticity. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A.

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Quiescence and γH2AX in neuroblastoma are regulated by ouabain/Na,K-ATPase

Hiyoshi H., Abdelhady S., Segerström L., Sveinbjörnsson B., Nuriya M., Lundgren T. K., Desfrere L., Miyakawa A., Yasui M., Kogner P., Johnsen J. I., Andäng M., Uhlén P.

British Journal of Cancer 106 ( 11 ) 1807 - 1815 2012.05

ISSN 0007-0920

Background: Cellular quiescence is a state of reversible proliferation arrest that is induced by anti-mitogenic signals. The endogenous cardiac glycoside ouabain is a specific ligand of the ubiquitous sodium pump, Na,K-ATPase, also known to regulate cell growth through unknown signalling pathways. Methods: To investigate the role of ouabain/Na,K-ATPase in uncontrolled neuroblastoma growth we used xenografts, flow cytometry, immunostaining, comet assay, real-time PCR, and electrophysiology after various treatment strategies. Results: The ouabain/Na,K-ATPase complex induced quiescence in malignant neuroblastoma. Tumour growth was reduced by >50% when neuroblastoma cells were xenografted into immune-deficient mice that were fed with ouabain. Ouabain-induced S-G2 phase arrest, activated the DNA-damage response (DDR) pathway marker γH2AX, increased the cell cycle regulator p21 ^Waf1/Cip1 and upregulated the quiescence-specific transcription factor hairy and enhancer of split1 (HES1), causing neuroblastoma cells to ultimately enter G0. Cells re-entered the cell cycle and resumed proliferation, without showing DNA damage, when ouabain was removed. Conclusion: These findings demonstrate a novel action of ouabain/Na,K-ATPase as a regulator of quiescence in neuroblastoma, suggesting that ouabain can be used in chemotherapies to suppress tumour growth and/or arrest cells to increase the therapeutic index in combination therapies. © 2012 Cancer Research UK.

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GluA4 is indispensable for driving fast neurotransmission across a high-fidelity central synapse

Yang Yi Mei, Aitoubah Jamila, Lauer Amanda M., Nuriya Mutsuo, Takamiya Kogo, Jia Zhengping, May Bradford J., Huganir Richard L., Wang Lu Yang

Journal of Physiology 589 ( 17 ) 4209 - 4227 2011.09

ISSN 0022-3751

Fast excitatory synaptic transmission in central synapses is mediated primarily by AMPA receptors (AMPARs), which are heteromeric assemblies of four subunits, GluA1-4. Among these subunits, rapidly gating GluA3/4 appears to be the most abundantly expressed to enable neurotransmission with submillisecond precision at fast rates in subsets of central synapses. However, neither definitive identification of the molecular substrate for native AMPARs in these neurons, nor their hypothesized functional roles in vivo has been unequivocally demonstrated, largely due to lack of specific antagonists. Using GluA3 or GluA4 knockout (KO) mice, we investigated these issues at the calyx of Held synapse, which is known as a high-fidelity synapse involved in sound localization. Patch-clamp recordings from postsynaptic neurons showed that deletion of GluA4 significantly slowed the time course of both evoked and miniature AMPAR-mediated excitatory postsynaptic currents (AMPAR-EPSCs), reduced their amplitude, and exacerbated AMPAR desensitization and short-term depression (STD). Surprisingly, presynaptic release probability was also elevated, contributing to severe STD at GluA4-KO synapses. In contrast, only marginal changes in AMPAR-EPSCs were found in GluA3-KO mice. Furthermore, independent of changes in intrinsic excitability of postsynaptic neurons, deletion of GluA4 markedly reduced synaptic drive and increased action potential failures during high-frequency activity, leading to profound deficits in specific components of the auditory brainstem responses associated with synchronized spiking in the calyx of Held synapse and other related neurons in vivo. These observations identify GluA4 as the main determinant for fast synaptic response, indispensable for driving high-fidelity neurotransmission and conveying precise temporal information. © 2011 The Authors. Journal compilation © 2011 The Physiological Society.

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Regulation of Kv2.1 phosphorylation in an animal model of anoxia

Ito Takashi, Nuriya Mutsuo, Yasui Masato

Neurobiology of Disease 38 ( 1 ) 85 - 91 2010.04

ISSN 0969-9961

Conditions such as hypoxia and anoxia inflict serious damage to the brain and continue to be major medical problems. However, the molecular mechanisms that give rise to such damage are not well understood. To elucidate these mechanisms, we established a clinically relevant rodent model of anoxia/recovery by monitoring blood gas levels after oxygen deprivation. Using this animal model, we examined the regulation of Kv2.1, a voltage-gated potassium channel that plays pivotal roles in the homeostasis and survival of neurons. We found that exposure to anoxia induces rapid dephosphorylation of Kv2.1 in the brain, which can be blocked by pre-administration of a NMDA-type glutamate receptor antagonist, memantine. Furthermore, this change is rapidly reversed as the animal recovers from anoxic stress. These results suggest that Kv2.1 is tightly regulated in a clinically relevant animal model of anoxia and further implicate its role in the homeostasis of neurons during anoxic stress. © 2010 Elsevier Inc. All rights reserved.

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Membrane potential dynamics of axons in cultured hippocampal neurons probed by second-harmonic-generation imaging

Nuriya Mutsuo, Yasui Masato

Journal of Biomedical Optics 15 ( 2 ) 2010

ISSN 1083-3668

The electrical properties of axons critically influence the nature of communication between neurons. However, due to their small size, direct measurement of membrane potential dynamics in intact and complex mammalian axons has been a challenge. Furthermore, quantitative optical measurements of axonal membrane potential dynamics have not been available. To characterize the basic principles of somatic voltage signal propagation in intact axonal arbors, second-harmonic-generation (SHG) imaging is applied to cultured mouse hippocampal neurons. When FM4-64 is applied extracellularly to dissociated neurons, whole axonal arbors are visualized by SHG imaging. Upon action potential generation by somatic current injection, nonattenuating action potentials are recorded in intact axonal arbors. Interestingly, however, both current-and voltage-clamp recordings suggest that nonregenerative subthreshold somatic voltage changes at the soma are poorly conveyed to these axonal sites. These results reveal the nature of membrane potential dynamics of cultured hippocampal neurons, and further show the possibility of SHG imaging in physiological investigations of axons. © 2010 Society of Photo-Optical Instrumentation Engineers.

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Activity-dependent regulation of HCN1 protein in cortical neurons

Arimitsu Takeshi, Nuriya Mutsuo, Ikeda Kazushige, Takahashi Takao, Yasui Masato

Biochemical and Biophysical Research Communications 387 ( 1 ) 87 - 91 2009.09

ISSN 0006-291X

Homeostasis of neuronal activity is crucial to neuronal physiology. In dendrites, hyperpolarization-activated cyclic nucleotide-gated channel (HCN) 1 is considered to play critical roles in this process. While electrophysiological studies have demonstrated the dynamic modulation of I_h current mediated by HCN1 proteins, little is known about the underlying molecular and cellular mechanisms. In this study, we utilized cortical cultured neurons and biochemical methods to identify molecular and cellular mechanisms that mediate the physiological regulation of HCN1 channel functions in cortical neurons. Pharmacological manipulations of neuronal activity resulted in changes in the expression level of HCN1. In addition, the surface expression of HCN1 was dynamically regulated by neuronal activity. Both of these changes led to functional modulations of HCN1 channels. Our study suggests that coordinated changes in protein expression and surface expression of HCN1 serve as the key regulatory mechanisms controlling the function of endogenous HCN1 protein in cortical neurons. © 2009 Elsevier Inc. All rights reserved.

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Drosophila big brain does not act as a water channel, but mediates cell adhesion

Tatsumi Kimiko, Tsuji Shoji, Miwa Hideki, Morisaku Toshinori, Nuriya Mutsuo, Orihara Minako, Kaneko Kazunari, Okano Hideyuki, Yasui Masato

FEBS Letters 583 ( 12 ) 2077 - 2082 2009.06

ISSN 0014-5793

The neurogenic gene Drosophila big brain (bib) has a high sequence homology to aquaporin-4. However, its cellular functions in Drosophila neurogenesis have remained elusive. Here we investigated cell adhesion, and the ion and water permeability of Bib. The adhesive function was examined by a cell aggregation assay using L cells. Bib-transfected L cells formed aggregated clusters, while control-L cells remained as a single cell suspension. Ion permeation was not confirmed in L cells stably expressing Bib. When expressed in COS7 cells, Bib exhibited limited water permeability. This newly found cell adhesive function of Bib may be important for Drosophila neurogenesis. © 2009 Federation of European Biochemical Societies.

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Phosphorylation in the C-terminal domain of Aquaporin-4 is required for Golgi transition in primary cultured astrocytes

Kadohira Ikuko, Abe Yoichiro, Nuriya Mutsuo, Sano Kazumi, Tsuji Shoji, Arimitsu Takeshi, Yoshimura Yasunori, Yasui Masato

Biochemical and Biophysical Research Communications 377 ( 2 ) 463 - 468 2008.12

ISSN 0006-291X

Aquaporin-4 (AQP4) is expressed in the perivascular and subpial astrocytes end-feet in mammalian brain, and plays a critical component of an integrated water and potassium homeostasis. Here we examine whether AQP4 is phosphorylated in primary cultured mouse astrocytes. Astrocytes were metabolically labeled with [³²P]phosphoric acid, then AQP4 was immunoprecipitated with anti-AQP4 antibody. We observed that AQP4 was constitutively phosphorylated, which is reduced by treatment with protein kinase CK2 inhibitors. To elucidate the phosphorylation of AQP4 by CK2, myc-tagged wild-type or mutant AQP4 was transiently transfected in primary cultured astrocytes. Substitution of Ala residues for four putative CK2 phosphorylation sites in the C terminus abolished the phosphorylation of AQP4. Immunofluorescent microscopy revealed that the quadruple mutant was localized in the Golgi apparatus. These observations indicate that the C-terminal domain of AQP4 is constitutively phosphorylated at least in part by protein kinase CK2 and it is required for Golgi transition. © 2008 Elsevier Inc. All rights reserved.

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Rapid and bi-directional regulation of AMPA receptor phosphorylation and trafficking by JNK

Thomas Gareth M., Lin Da Ting, Nuriya Mutsuo, Huganir Richard L.

EMBO Journal 27 ( 2 ) 361 - 372 2008.01

ISSN 0261-4189

Some Rights Reserved.Jun N-terminal kinases (JNKs) are implicated in various neuropathological conditions. However, physiological roles for JNKs in neurons remain largely unknown, despite the high expression level of JNKs in brain. Here, using bioinformatic and biochemical approaches, we identify the AMPA receptor GluR2L and GluR4 subunits as novel physiological JNK substrates in vitro, in heterologous cells and in neurons. Consistent with this finding, GluR2L and GluR4 associate with specific JNK signaling components in the brain. Moreover, the modulation of the novel JNK sites in GluR2L and GluR4 is dynamic and bi-directional, such that phosphorylation and de-phosphorylation are triggered within minutes following decreases and increases in neuronal activity, respectively. Using live-imaging techniques to address the functional consequence of these activity-dependent changes we demonstrate that the novel JNK site in GluR2L controls reinsertion of internalized GluR2L back to the cell surface following NMDA treatment, without affecting basal GluR2L trafficking. Taken together, our results demonstrate that JNK directly regulates AMPA-R trafficking following changes in neuronal activity in a rapid and bi-directional manner. © 2008 European Molecular Biology Organization

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