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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>
N-Methyl Amine-substituted Fluoxetine Derivatives: New Dopamine Transporter Inhibitors
Young Sil Yoon,Taesup Cho,Sung-Hwa Yoon,Churl Ki Min,Changho Lee 대한약학회 2009 Archives of Pharmacal Research Vol.32 No.12
Transport of dopamine (DA) by the dopamine transporter from the synaptic cleft into the presynaptic terminals plays a key role in terminating dopaminergic neurotransmission. The binding of psychostimulants to their recognition sites on the DA transporter leads to an inhibition of DA transport and a subsequent rising of the dopamine contents in the synaptic cleft is ascribed to a mode of psychostimulation. Discovery of dopamine transporter inhibitors would be useful with regard to substituting for cocaine and minimizing its abuse. Recently, a number of fluoxetine analogues were synthesized, especially focusing on the substitution of N-methyl amine group through modifying the structure of the fluoxetine, N-methyl-3-[p-trifluoromethylphenoxy]-3-phenylpropylamine, widely used as an antidepressant. Among them, the pharmacological properties of FD-2, (R)-N-ethanol-3-(4-trifluorophenoxy)-3-phenyl propaneamine and FD-4, N-(R)-3-trifluorophenoxy-3-phenylpropane-imidazole with a higher affinity for the DA transporter were characterized in terms of dopamine transporter inhibition expecting for useful cocaine substitutes. Effects of the compounds on [H3]dopamine uptake, [I125]RTI-55 binding, and DA transporter-associated currents were examined with the ligand binding assays and voltage clamping technique in human embryonic kidney (HEK)-293 cells where the recombinant human DA transporter (hDAT) was stably expressed. Our results showed that (i) fluoxetine was potent in inhibiting both the uptake of [H3]DA (IC50 = 0.21 ± 0.032 mM, n = 3) and the [I125]RTI-55 binding (IC50 = 0.23 ± 0.012 mM, n = 10); (ii) N-methyl amine substituted fluoxetine analogues, FD-2 and FD-4 were equally or more potent than fluoxetine itself in terms of inhibition of [H3]DA uptake (IC50 FD-2: 0.077 ± 0.0032 mM (n = 3); FD-4: 0.26 ± 0.13 mM (n = 3), inhibition of [I125]RTI-55 binding, and reduction in DA transporter-associated currents, suggesting that these analogues could be a new class of dopamine transporter inhibitors.
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.