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C. Justin Lee,윤보은 한국통합생물학회 2014 Animal cells and systems Vol.18 No.4
γ-amino butyric acid (GABA) is the main transmitter mediating inhibitory synaptic transmission in the brain and is releasednot only from a subset of neurons but also from astrocytes. It has been well established that GABA is released via Ca2+-dependent exocytosis of GABA-containing vesicles in neurons. However, a novel form of GABA release in astrocytes viathe Ca2+-activated anion channel, Bestrophin-1 (Best1), has been recently reported. In here, we reveal a novel anionchannel-mediated GABA release mechanism in cultured cortical astrocytes pretreated with GABA. We have observed thatcultured cortical astrocytes do not contain much GABA. We demonstrate in these same astrocytes, pretreated with GABA,that activation of the protease-activated receptor 1 (PAR1) produces an increase in intracellular Ca2+ concentration thatleads to opening of Best1 channels and the subsequent release of GABA. These results provide strong molecular evidencefor a potential astrocyte–neuron interaction via PAR1-induced and Best1-mediated GABA release.
Ca <sup>2+</sup> Entry is Required for Mechanical Stimulation-induced ATP Release from Astrocyte
Lee, Jaekwang,Chun, Ye-Eun,Han, Kyung-Seok,Lee, Jungmoo,Woo, Dong Ho,Lee, C. Justin The Korean Society for Brain and Neural Science 2015 Experimental Neurobiology Vol.24 No.1
<P>Astrocytes and neurons are inseparable partners in the brain. Neurotransmitters released from neurons activate corresponding G protein-coupled receptors (GPCR) expressed in astrocytes, resulting in release of gliotransmitters such as glutamate, D-serine, and ATP. These gliotransmitters in turn influence neuronal excitability and synaptic activities. Among these gliotransmitters, ATP regulates the level of network excitability and is critically involved in sleep homeostasis and astrocytic Ca<SUP>2+</SUP> oscillations. ATP is known to be released from astrocytes by Ca<SUP>2+</SUP>-dependent manner. However, the precise source of Ca<SUP>2+</SUP>, whether it is Ca<SUP>2+</SUP> entry from outside of cell or from the intracellular store, is still not clear yet. Here, we performed sniffer patch to detect ATP release from astrocyte by using various stimulation. We found that ATP was not released from astrocyte when Ca<SUP>2+</SUP> was released from intracellular stores by activation of Gα<SUB>q</SUB>-coupled GPCR including PAR1, P2YR, and B2R. More importantly, mechanical stimulation (MS)-induced ATP release from astrocyte was eliminated when external Ca<SUP>2+</SUP> was omitted. Our results suggest that Ca<SUP>2+</SUP> entry, but not release from intracellular Ca<SUP>2+</SUP> store, is critical for MS-induced ATP release from astrocyte.</P>
GluA1 phosphorylation at serine 831 in the lateral amygdala is required for fear renewal
Lee, Sukwon,Song, Beomjong,Kim, Jeongyeon,Park, Kyungjoon,Hong, Ingie,An, Bobae,Song, Sangho,Lee, Jiwon,Park, Sungmo,Kim, Jihye,Park, Dongeun,Lee, C Justin,Kim, Kyungjin,Shin, Ki Soon,Tsien, Richard W Nature Publishing Group, a division of Macmillan P 2013 NATURE NEUROSCIENCE Vol.16 No.10
Fear renewal, a widely pursued model of post-traumatic stress disorder and phobias, refers to the context-specific relapse of conditioned fear after extinction. However, its molecular mechanisms are largely unknown. We found that renewal-inducing stimuli, generally believed to be insufficient to induce synaptic plasticity, enhanced excitatory synaptic strength, activity of synaptic GluA2-lacking AMPA receptors and Ser831 phosphorylation of synaptic surface GluA1 in the lateral nucleus of the amygdala (LAn) of fear-extinguished rats. Consistently, the induction threshold for LAn synaptic potentiation was considerably lowered after extinction, and renewal occluded this low-threshold potentiation. The low-threshold potentiation (a potential cellular substrate for renewal), but not long-term potentiation, was attenuated by dialysis into LAn neurons of a GluA1-derived peptide that competes with Ser831-phosphorylated GluA1. Microinjections of the same peptide into the LAn attenuated fear renewal, but not fear learning. Our findings suggest that GluA1 phosphorylation constitutes a promising target for clinical treatment of aberrant fear-related disorders.
Lee, Young,Han, Na-Eun,Kim, Wonju,Kim, Jae Gon,Lee, In Bum,Choi, Su Jeong,Chun, Heejung,Seo, Misun,Lee, C. Justin,Koh, Hae-Young,Kim, Joung-Hun,Baik, Ja-Hyun,Bear, Mark F.,Choi, Se-Young,Yoon, Bong-Ju Korean Society for Molecular and Cellular Biology 2020 Molecules and cells Vol.43 No.4
The basal ganglia network has been implicated in the control of adaptive behavior, possibly by integrating motor learning and motivational processes. Both positive and negative reinforcement appear to shape our behavioral adaptation by modulating the function of the basal ganglia. Here, we examined a transgenic mouse line (G2CT) in which synaptic transmissions onto the medium spiny neurons (MSNs) of the basal ganglia are depressed. We found that the level of collaterals from direct pathway MSNs in the external segment of the globus pallidus (GPe) ('bridging collaterals') was decreased in these mice, and this was accompanied by behavioral inhibition under stress. Furthermore, additional manipulations that could further decrease or restore the level of the bridging collaterals resulted in an increase in behavioral inhibition or active behavior in the G2CT mice, respectively. Collectively, our data indicate that the striatum of the basal ganglia network integrates negative emotions and controls appropriate coping responses in which the bridging collateral connections in the GPe play a critical regulatory role.
Romo1 is a mitochondrial nonselective cation channel with viroporin-like characteristics
Lee, Gi Young,You, Deok-gyun,Lee, Hye-Ra,Hwang, Sun Wook,Lee, C. Justin,Yoo, Young Do Rockefeller University Press 2018 The Journal of cell biology Vol.217 No.6
<P>Reactive oxygen species (ROS) modulator 1 (Romo1) is a nuclear-encoded mitochondrial inner membrane protein known to regulate mitochondrial ROS production and to act as an essential redox sensor in mitochondrial dynamics. Although its physiological roles have been studied for a decade, the biophysical mechanisms that explain these activities of Romo1 are unclear. In this study, we report that Romo1 is a unique mitochondrial ion channel that differs from currently identified eukaryotic ion channels. Romo1 is a highly conserved protein with structural features of class II viroporins, which are virus-encoded nonselective cation channels. Indeed, Romo1 forms a nonselective cation channel with its amphipathic helical transmembrane domain necessary for pore-forming activity. Notably, channel activity was specifically inhibited by Fe<SUP>2+</SUP> ions, an essential transition metal ion in ROS metabolism. Using structural bioinformatics, we designed an experimental data–guided structural model of Romo1 with a rational hexameric structure. We propose that Romo1 establishes a new category of viroporin-like nonselective cation channel in eukaryotes.</P>
Lee, Mihye,Paik, Sang Kyoo,Lee, Min-Jung,Kim, Yoon-Jung,Kim, Sungdae,Nahm, Minyeop,Oh, Soo-Jin,Kim, Hyun-Man,Yim, Jeongbin,Lee, C. Justin,Bae, Yong Chul,Lee, Seungbok Elsevier 2009 Developmental Biology Vol.330 No.2
<P><B>Abstract</B></P><P>Hereditary spastic paraplegia (HSP) is an inherited neurological disorder characterized by progressive spasticity and weakness of the lower extremities. The most common early-onset form of HSP is caused by mutations in the human gene that encodes the dynamin-family GTPase Atlastin-1 (Atl-1). Recently, loss of the <I>Drosophila</I> ortholog of Atl-1 (Atl) has been found to induce locomotor impairments from the earliest adult stages, suggesting the developmental role of atlastin-subfamily GTPases. Here, we provide evidence that Atl is required for normal growth of muscles and synapses at the neuromuscular junction (NMJ). Atl protein is highly expressed in larval body-wall muscles. Loss-of-function mutations in the <I>atl</I> gene reduce the size of muscles and increase the number of synaptic boutons. Rescue of these defects is accomplished by muscular, but not neuronal expression of Atl. Loss of Atl also disrupts ER and Golgi morphogenesis in muscles and reduces the synaptic levels of the scaffold proteins Dlg and α-spectrin. We also provide evidence that Atl functions with the microtubule-severing protein Spastin to disassemble microtubules in muscles. Finally, we demonstrate that the microtubule-destabilizing drug vinblastine alleviates synapse and muscle defects in <I>atl</I> mutants. Together, our results suggest that Atl controls synapse development and ER and Golgi morphogenesis by regulating microtubule stability.</P>
Generation of Best1 knockdown mice using lentiviral vector expressing small hairpin RNA
Lee, C. Justin,Min, Joo Ok,Yoon, Bo-Eun 한국통합생물학회 2014 Animal cells and systems Vol.18 No.3
We demonstrate that pronuclear injection of lentiviral vectors expressing small hairpin RNAs (shRNAs) that silence the expression of specific genes can be used to generate knockdown mice. A lentiviral vector capable of generating shRNA that is specific for the target gene bestrophin 1 (Best1) encodes for an anion channel that is permeable to glutamate and gamma amino butyric acid (GABA) and that also regulates intracellular calcium signaling. We confirmed that cultured cerebellar glia from these Best1 knockdown mice showed attenuation of GABA release induced by an increase in intracellular calcium. Therefore, we propose that a combined approach, the use of transgenesis together with lentiviral vectors expressing shRNAs, can successfully generate a large number of mice in which the expression of a specific gene can be downregulated gradually. We also suggest that the Best1 knockdown mouse can be a useful tool for studying Best1 gene function.