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Seo, Bo Am,Cho, Taesup,Lee, Daniel Z.,Lee, Joong-jae,Lee, Boyoung,Kim, Seong-Wook,Shin, Hee-Sup,Kang, Myoung-Goo National Academy of Sciences 2018 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.115 No.27
<P>Mutations in the human LARGE gene result in severe intellectual disability and muscular dystrophy. How LARGE mutation leads to intellectual disability, however, is unclear. In our proteomic study, LARGE was found to be a component of the AMPA-type glutamate receptor (AMPA-R) protein complex, a main player for learning and memory in the brain. Here, our functional study of LARGE showed that LARGE at the Golgi apparatus (Golgi) negatively controlled AMPA-R trafficking from the Golgi to the plasma membrane, leading to down-regulated surface and synaptic AMPA-R targeting. In LARGE knockdown mice, long-term potentiation (LTP) was occluded by synaptic AMPA-R overloading, resulting in impaired contextual fear memory. These findings indicate that the fine-tuning of AMPAR trafficking by LARGE at the Golgi is critical for hippocampus-dependent memory in the brain. Our study thus provides insights into the pathophysiology underlying cognitive deficits in brain disorders associated with intellectual disability.</P>
Optogenetic control of endogenous Ca<sup>2+</sup> channels in vivo
Kyung, Taeyoon,Lee, Sangkyu,Kim, Jung Eun,Cho, Taesup,Park, Hyerim,Jeong, Yun-Mi,Kim, Dongkyu,Shin, Anna,Kim, Sungsoo,Baek, Jinhee,Kim, Jihoon,Kim, Na Yeon,Woo, Doyeon,Chae, Sujin,Kim, Cheol-Hee,Shin, Nature Publishing Group, a division of Macmillan P 2015 Nature biotechnology Vol.33 No.10
Calcium (Ca<SUP>2+</SUP>) signals that are precisely modulated in space and time mediate a myriad of cellular processes, including contraction, excitation, growth, differentiation and apoptosis. However, study of Ca<SUP>2+</SUP> responses has been hampered by technological limitations of existing Ca<SUP>2+</SUP>-modulating tools. Here we present OptoSTIM1, an optogenetic tool for manipulating intracellular Ca<SUP>2+</SUP> levels through activation of Ca<SUP>2+</SUP>-selective endogenous Ca<SUP>2+</SUP> release−activated Ca<SUP>2+</SUP> (CRAC) channels. Using OptoSTIM1, which combines a plant photoreceptor and the CRAC channel regulator STIM1 (ref. 4), we quantitatively and qualitatively controlled intracellular Ca<SUP>2+</SUP> levels in various biological systems, including zebrafish embryos and human embryonic stem cells. We demonstrate that activating OptoSTIM1 in the CA1 hippocampal region of mice selectively reinforced contextual memory formation. The broad utility of OptoSTIM1 will expand our mechanistic understanding of numerous Ca<SUP>2+</SUP>-associated processes and facilitate screening for drug candidates that antagonize Ca<SUP>2+</SUP> signals.