Akiko Nakano-Kobayashi

Publications (6)56.21 Total impact

• Article: Rapid synthesis of the X-linked mental retardation protein OPHN1 mediates mGluR-dependent LTD through interaction with the endocytic machinery.

  Nael Nadif Kasri, Akiko Nakano-Kobayashi, Linda Van Aelst
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  ABSTRACT: Activation of group I metabotropic glutamate receptors leads to long-term depression (mGluR-LTD). Alterations in this form of plasticity have been linked to drug addiction and cognitive disorders. A key characteristic of mGluR-LTD is its dependence on rapid protein synthesis; however, the identities of the proteins mediating LTD remain elusive. Here, we identify the X-linked mental retardation protein OPHN1 as a molecule essential for mGluR-LTD in the hippocampus. mGluR-LTD induction elicits rapid dendritic OPHN1 synthesis, which is dependent on mGluR1 activation and independent of fragile X mental retardation protein (FMRP). This response is essential for mGluR-LTD, as acute blockade of OPHN1 synthesis impedes LTD. mGluR-induced OPHN1 mediates LTD and associated persistent decreases in surface AMPARs via interactions with endophilin A2/3. Importantly, this role of OPHN1 is separable from its effects on basal synaptic strength, which require OPHN1's Rho-GAP activity and interaction with Homer1b/c. Thus, our data establish a role for rapid OPHN1 synthesis in mGluR-LTD. VIDEO ABSTRACT:
  Neuron 10/2011; 72(2):300-15. · 14.74 Impact Factor
• Article: The Rho-linked mental retardation protein oligophrenin-1 controls synapse maturation and plasticity by stabilizing AMPA receptors.

  Nael Nadif Kasri, Akiko Nakano-Kobayashi, Roberto Malinow, Bo Li, Linda Van Aelst
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  ABSTRACT: Oligophrenin-1 (OPHN1) encodes a Rho-GTPase-activating protein (Rho-GAP) whose loss of function has been associated with X-linked mental retardation (MR). The pathophysiological role of OPHN1, however, remains poorly understood. Here we show that OPHN1 through its Rho-GAP activity plays a critical role in the activity-dependent maturation and plasticity of excitatory synapses by controlling their structural and functional stability. Synaptic activity through NMDA receptor activation drives OPHN1 into dendritic spines, where it forms a complex with AMPA receptors, and selectively enhances AMPA-receptor-mediated synaptic transmission and spine size by stabilizing synaptic AMPA receptors. Consequently, decreased or defective OPHN1 signaling prevents glutamatergic synapse maturation and causes loss of synaptic structure, function, and plasticity. These results imply that normal activity-driven glutamatergic synapse development is impaired by perturbation of OPHN1 function. Thus, our findings link genetic deficits in OPHN1 to glutamatergic dysfunction and suggest that defects in early circuitry development are an important contributory factor to this form of MR.
  Genes & development 07/2009; 23(11):1289-302. · 12.08 Impact Factor
• Article: The Rho-linked mental retardation protein OPHN1 controls synaptic vesicle endocytosis via endophilin A1.

  Akiko Nakano-Kobayashi, Nael Nadif Kasri, Sarah E Newey, Linda Van Aelst
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  ABSTRACT: Neurons transmit information at chemical synapses by releasing neurotransmitters that are stored in synaptic vesicles (SVs) at the presynaptic site. After release, these vesicles need to be efficiently retrieved in order to maintain synaptic transmission. In concurrence, malfunctions in SV recycling have been associated with cognitive disorders. Oligophrenin-1 (OPHN1) encodes a Rho-GTPase-activating protein (Rho-GAP) whose loss of function causes X-linked mental retardation. OPHN1 is highly expressed in the brain and present both pre- and postsynaptically in neurons. Previous studies report that postsynaptic OPHN1 is important for dendritic spine morphogenesis, but its function at the presynaptic site remains largely unexplored. Here, we present evidence that reduced or defective OPHN1 signaling impairs SV cycling at hippocampal synapses. In particular, we show that OPHN1 knockdown affects the kinetic efficiency of endocytosis. We further demonstrate that OPHN1 forms a complex with endophilin A1, a protein implicated in membrane curvature generation during SV endocytosis and, importantly, that OPHN1's interaction with endophilin A1 and its Rho-GAP activity are important for its function in SV endocytosis. Our findings suggest that defects in efficient SV retrieval may contribute to the pathogenesis of OPHN1-linked cognitive impairment.
  Current biology: CB 06/2009; 19(13):1133-9. · 10.99 Impact Factor
• Article: Novel activation mechanism and physiological function of PIP5Kgamma661.

  Yasunori Kanaho, Akiko Nakano-Kobayashi, Takeaki Yokozeki
  Advances in enzyme regulation 04/2008; 48:88-96.
• Article: Role of activation of PIP5Kgamma661 by AP-2 complex in synaptic vesicle endocytosis.

  Akiko Nakano-Kobayashi, Masakazu Yamazaki, Takamitsu Unoki, Tsunaki Hongu, Chie Murata, Ryo Taguchi, Toshiaki Katada, Michael A Frohman, Takeaki Yokozeki, Yasunori Kanaho
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  ABSTRACT: Synaptic vesicles (SVs) are retrieved by clathrin-mediated endocytosis at the nerve terminals. Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] drives this event by recruiting the components of the endocytic machinery. However, the molecular mechanisms that result in local generation of PI(4,5)P2 remain unclear. We demonstrate here that AP-2 complex directly interacts with phosphatidylinositol 4-phosphate 5-kinase gamma661 (PIP5Kgamma661), the major PI(4,5)P2-producing enzyme in the brain. The beta2 subunit of AP-2 was found to bind to the C-terminal tail of PIP5Kgamma661 and cause PIP5Kgamma661 activation. The interaction is regulated by PIP5Kgamma661 dephosphorylation, which is triggered by depolarization in mouse hippocampal neurons. Finally, overexpression of the PIP5Kgamma661 C-terminal region in hippocampal neurons suppresses depolarization-dependent SV endocytosis. These findings provide evidence for the molecular mechanism through which PIP5Kgamma661 locally generates PI(4,5)P2 in hippocampal neurons and suggest a model in which the interaction trigger SV endocytosis.
  The EMBO Journal 03/2007; 26(4):1105-16. · 9.20 Impact Factor
• Article: Role of activation of PIP5K|[gamma]|661 by AP-2 complex in synaptic vesicle endocytosis

  Akiko Nakano-Kobayashi, Masakazu Yamazaki, Takamitsu Unoki, Tsunaki Hongu, Chie Murata, Ryo Taguchi, Toshiaki Katada, Michael A Frohman, Takeaki Yokozeki, Yasunori Kanaho
  [show abstract] [hide abstract]
  ABSTRACT: Synaptic vesicles (SVs) are retrieved by clathrin-mediated endocytosis at the nerve terminals. Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] drives this event by recruiting the components of the endocytic machinery. However, the molecular mechanisms that result in local generation of PI(4,5)P2 remain unclear. We demonstrate here that AP-2 complex directly interacts with phosphatidylinositol 4-phosphate 5-kinase 661 (PIP5K661), the major PI(4,5)P2-producing enzyme in the brain. The 2 subunit of AP-2 was found to bind to the C-terminal tail of PIP5K661 and cause PIP5K661 activation. The interaction is regulated by PIP5K661 dephosphorylation, which is triggered by depolarization in mouse hippocampal neurons. Finally, overexpression of the PIP5K661 C-terminal region in hippocampal neurons suppresses depolarization-dependent SV endocytosis. These findings provide evidence for the molecular mechanism through which PIP5K661 locally generates PI(4,5)P2 in hippocampal neurons and suggest a model in which the interaction trigger SV endocytosis.
  The EMBO Journal 02/2007; 26(4):1105-1116. · 9.20 Impact Factor