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Research Highlights

Glutamatergic Signal Transduction: Glutamate transport & Epilepsy

Glutamate plays an essential role in the chemical transmission in brain. Glutamate is accumulated in the synaptic vesicles of nerve terminal and is released by appropriate signal input. The vesicular glutamate transporter (VGLUT) is a key component for such signal transmission since it transports glutamate into synaptic vesicles. Recent our biochemical analysis revealed that VGLUT is regulated by chloride ion and ketone bodies that is metabolic products of fasting or ketogenic diet. Our finding unveiled novel relationships of neuronal signal transmission and metabolic state.

Yoshinori Moriyama, Department of Membrane Biochemistry Reference: Juge et al., Neuron 68: 99-112, 2010. More Detail  

A novel modulatory ‘on-off’ system for PI 3-kinase-Akt signaling through S-nitrosylation of PTEN

Nitric oxide (NO) exerts pleiotropic cellular responses on proliferation, apoptosis, neurotransmission, and neurotoxicity in several types of cells by means of protein S-nitrosylation. Several methods have been published to detect S-nitrosylated proteins (SNO-Ps) by using antibodies, photolysis, and mercury affinity. In particular, the biotin-switch assay is a modified immunoblot developed by Jaffrey and Snyder that has been commonly used to detect endogenous SNO-Ps; this method has greatly advanced the field. Although a number of proteins have been identified as substrates for S-nitrosylation in the past several years, we hypothesized that many more candidates modified by physiological levels of NO might still remain to be identified. We attempted to isolate SNO-Ps in physiological condition by an antibody array. We found that phosphatase with sequence homology to tensin (PTEN) is preferentially S-nitrosylated by low concentrations of NO. Our results suggest that inhibition of PTEN activity through S-nitrosylation augments Akt signaling, thereby contributing to cell survival in ischemic brains.

Takashi Uehara, Department of Medicinal Pharmacology Reference: Numajiri et al., Proc. Natl. Acad. Sci. USA 108:10349- 10354, 2011 More Detail

Molecular basis of multimodal regulation of a TRP channel

Transient receptor potential (TRP) channels play important roles for sensing diverse environmental stimuli in our body, such as temperature, chemical substances, and osmolarity. They also serve as receptors for pain sensation. One of the significant characteristics of the functions of TRP channels is a multimodal activation by various stimuli: even a single channel can respond to different kinds of chemical and mechanical stimuli. We identified a fungal TRP channel exhibiting activation by hyperosmolarity, temperature-increase, cytosolic Ca2+-elevation, membrane-potential and oxidizer application, and thus it is expected to represent as a prototypic multimodal TRP channel. The channel was found to possess a cytosolic C-terminal domain, primarily composed of intrinsically disordered regions with multiple regulatory modules. The integrated approaches with biochemical, physiological, crystallographic, and NMR spectroscopic analyses revealed the structural and functional correlations between dynamic and flexible structural characteristics of the cytosolic domain and the multimodal regulation of the channel activities.

Atsuko Yamashita, Department of Structural Biology Reference: Ihara et al., J. Biol. Chem. 288, 15303-15317, 2013 More detail

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