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Yoo, Jae Cheal,Park, Nammi,Choi, Hye Young,Park, Jae-Yong,Yi, Gwan-Su Academic Press 2018 Biochemical and biophysical research communication Vol. No.
<P><B>Abstract</B></P> <P>Copine1 (CPNE1), has tandem C2 domains and an A domain. We previously demonstrated that CPNE1 directly induces neuronal differentiation via Protein kinase B (AKT) phosphorylation in the hippocampal progenitor cell line, HiB5. To better understand its cellular function, we carried out a yeast two-hybrid screening to find CPNE1 binding partners. Among the identified proteins, Jun activation domain-binding protein 1 (JAB1) appears to directly interact with CPNE1. Between CPNE1 and JAB1, the physical interaction was confirmed <I>in vitro</I> and <I>in vivo</I>. In addition the specific binding regions of CPNE1 and JAB1 was confirmed with truncated mutant assay. Furthermore, our results also demonstrate that AKT phosphorylation and expression of the neuronal marker protein are increased when JAB1 is overexpressed in CPNE1 high expressed HiB5 cells. Moreover, overexpression of both CPNE1 and JAB1 in HiB5 cells effectively increased neurite outgrowth.</P> <P>Collectively, our findings suggest that JAB1 activates the neuronal differentiation ability of CPNE1 through the binding of C2A domain in CPNE1 with MPN domain in JAB1.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Physical interaction of Copine1 and JAB1 was confirmed <I>in vitro</I> and <I>in vivo</I>. </LI> <LI> C2A domain in CPNE1 is critical for JAB1 binding. </LI> <LI> MPN domain in JAB1 has important role in binding with CPNE1. </LI> <LI> JAB1 regulates the CPNE1 mediated differentiation signaling pathway. </LI> </UL> </P>
Yarishkin, Oleg V.,Hwang, Eun-Mi,Kim, Dong-Gyu,Yoo, Jae-Cheal,Kang, Sang-Soo,Kim, Deok-Ryoung,Shin, Jae-Hee-Jung,Chung, Hye-Joo,Jeong, Ho-Sang,Kang, Da-Won,Han, Jae-Hee,Park, Jae-Yong,Hong, Seong-Geun The Korean Society of Pharmacology 2009 The Korean Journal of Physiology & Pharmacology Vol.13 No.6
A non-steroidal anti-inflammatory drug (NSAID) has many adverse effects including cardiovascular (CV) risk. Diclofenac among the nonselective NSAIDs has the highest CV risk such as congestive heart failure, which resulted commonly from the impaired cardiac pumping due to a disrupted excitationcontraction (E-C) coupling. We investigated the effects of diclofenac on the L-type calcium channels which are essential to the E-C coupling at the level of single ventricular myocytes isolated from neonatal rat heart, using the whole-cell voltage-clamp technique. Only diclofenac of three NSAIDs, including naproxen and ibuprofen, significantly reduced inward whole cell currents. At concentrations higher than $3\;{\mu}M$, diclofenac inhibited reversibly the $Na^+$ current and did irreversibly the L-type $Ca^{2+}$ channels-mediated inward current $(IC_{50}=12.89\pm0.43\;{\mu}M)$ in a dose-dependent manner. However, nifedipine, a well-known L-type channel blocker, effectively inhibited the L-type $Ca^{2+}$ currents but not the $Na^+$ current. Our finding may explain that diclofenac causes the CV risk by the inhibition of L-type $Ca^{2+}$ channel, leading to the impairment of E-C coupling in cardiac myocytes.
Acute Hypoxia Activates an ENaC-like Channel in Rat Pheochromocytoma (PC12) Cells
Yeon Ju Bae,Jae-Cheal Yoo,Nammi Park,Dawon Kang,Jaehee Han,Eunmi Hwang,Jae-Yong Park,Seong-Geun Hong 대한생리학회-대한약리학회 2013 The Korean Journal of Physiology & Pharmacology Vol.17 No.1
Cells can resist and even recover from stress induced by acute hypoxia, whereas chronic hypoxia often leads to irreversible damage and eventually death. Although little is known about the response(s) to acute hypoxia in neuronal cells, alterations in ion channel activity could be preferential. This study aimed to elucidate which channel type is involved in the response to acute hypoxia in rat pheochromocytomal (PC12) cells as a neuronal cell model. Using perfusing solution saturated with 95% N<sub>2</sub> and 5% CO<sub>2</sub>, induction of cell hypoxia was confirmed based on increased intracellular Ca<sup>2+ </sup>with diminished oxygen content in the perfusate. During acute hypoxia, one channel type with a conductance of about 30 pS (2.5 pA atₐ80 mV) was activated within the first 2~3 min following onset of hypoxia and was long-lived for more than 300 ms with high open probability (P<sub>o</sub>, up to 0.8). This channel was permeable to Na<sup>+</sup> ions, but not to K<sup>+</sup>, Ca<sup>+</sup>, and Cl<sup>ₐ</sup> ions, and was sensitively blocked by amiloride (200 nM). These characteristics and behaviors were quite similar to those of epithelial sodium channel (ENaC). RT-PCR and Western blot analyses confirmed that ENaC channel was endogenously expressed in PC12 cells. Taken together, a 30-pS ENaC-like channel was activated in response to acute hypoxia in PC12 cells. This is the first evidence of an acute hypoxia-activated Na<sup>+</sup> channel that can contribute to depolarization of the cell.
Acute Hypoxia Activates an ENaC-like Channel in Rat Pheochromocytoma (PC12) Cells
Bae, Yeon Ju,Yoo, Jae-Cheal,Park, Nammi,Kang, Dawon,Han, Jaehee,Hwang, Eunmi,Park, Jae-Yong,Hong, Seong-Geun The Korean Society of Pharmacology 2013 The Korean Journal of Physiology & Pharmacology Vol.17 No.1
Cells can resist and even recover from stress induced by acute hypoxia, whereas chronic hypoxia often leads to irreversible damage and eventually death. Although little is known about the response(s) to acute hypoxia in neuronal cells, alterations in ion channel activity could be preferential. This study aimed to elucidate which channel type is involved in the response to acute hypoxia in rat pheochromocytomal (PC12) cells as a neuronal cell model. Using perfusing solution saturated with 95% $N_2$ and 5% $CO_2$, induction of cell hypoxia was confirmed based on increased intracellular $Ca^{2+}$ with diminished oxygen content in the perfusate. During acute hypoxia, one channel type with a conductance of about 30 pS (2.5 pA at -80 mV) was activated within the first 2~3 min following onset of hypoxia and was long-lived for more than 300 ms with high open probability ($P_o$, up to 0.8). This channel was permeable to $Na^+$ ions, but not to $K^+$, $Ca^+$, and $Cl^-$ ions, and was sensitively blocked by amiloride (200 nM). These characteristics and behaviors were quite similar to those of epithelial sodium channel (ENaC). RT-PCR and Western blot analyses confirmed that ENaC channel was endogenously expressed in PC12 cells. Taken together, a 30-pS ENaC-like channel was activated in response to acute hypoxia in PC12 cells. This is the first evidence of an acute hypoxia-activated $Na^+$ channel that can contribute to depolarization of the cell.
Copine1 regulates neural stem cell functions during brain development
Kim, Tae Hwan,Sung, Soo-Eun,Cheal Yoo, Jae,Park, Jae-Yong,Yi, Gwan-su,Heo, Jun Young,Lee, Jae-Ran,Kim, Nam-Soon,Lee, Da Yong Elsevier 2018 Biochemical and biophysical research communication Vol.495 No.1
<P><B>Abstract</B></P> <P>Copine 1 (CPNE1) is a well-known phospholipid binding protein in plasma membrane of various cell types. In brain cells, CPNE1 is closely associated with AKT signaling pathway, which is important for neural stem cell (NSC) functions during brain development. Here, we investigated the role of CPNE1 in the regulation of brain NSC functions during brain development and determined its underlying mechanism. In this study, abundant expression of CPNE1 was observed in neural lineage cells including NSCs and immature neurons in human. With mouse brain tissues in various developmental stages, we found that CPNE1 expression was higher at early embryonic stages compared to postnatal and adult stages. To model developing brain in vitro, we used primary NSCs derived from mouse embryonic hippocampus. Our in vitro study shows decreased proliferation and multi-lineage differentiation potential in CPNE1 deficient NSCs. Finally, we found that the deficiency of CPNE1 downregulated mTOR signaling in embryonic NSCs. These data demonstrate that CPNE1 plays a key role in the regulation of NSC functions through the activation of AKT-mTOR signaling pathway during brain development.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Copine1 is highly expressed in neural lineage cells at early developmental stages. </LI> <LI> Copine1 regulates the proliferation of embryonic neural stem cells (NSCs). </LI> <LI> Copine1 regulates the differentiation of NSCs into neuronal and glial lineages. </LI> <LI> mTOR signaling pathway is involved in Copine1-meidated neural development. </LI> </UL> </P>
Li, Yi,Jung, Nan-Young,Yoo, Jae Cheal,Kim, Yul,Yi, Gwan-Su The Korean Society of Applied Pharmacology 2018 Biomolecules & Therapeutics(구 응용약물학회지) Vol.26 No.5
The phosphorylation of JNK is known to induce insulin resistance in insulin target tissues. The inhibition of JNK-JIP1 interaction, which interferes JNK phosphorylation, becomes a potential target for drug development of type 2 diabetes. To discover the inhibitors of JNK-JIP1 interaction, we screened out 30 candidates from 4320 compound library with In Cell Interaction Trap method. The candidates were further confirmed and narrowed down to five compounds using the FRET method in a model cell. Among those five compounds, Acebutolol showed notable inhibition of JNK phosphorylation and elevation of glucose uptake in diabetic models of adipocyte and liver cell. Structural computation showed that the binding affinity of Acebutolol on the JNK-JIP1 interaction site was comparable to the known inhibitor, BI-78D3. Our results suggest that Acebutolol, an FDA-approved beta blocker for hypertension therapy, could have a new repurposed effect on type 2 diabetes elevating glucose uptake process by inhibiting JNK-JIP1 interaction.
( Yi Li ),( Nan-young Jung ),( Jae Cheal Yoo ),( Yul Kim ),( Gwan-su Yi ) 한국응용약물학회 2018 Biomolecules & Therapeutics(구 응용약물학회지) Vol.26 No.5
The phosphorylation of JNK is known to induce insulin resistance in insulin target tissues. The inhibition of JNK-JIP1 interaction, which interferes JNK phosphorylation, becomes a potential target for drug development of type 2 diabetes. To discover the inhibitors of JNK-JIP1 interaction, we screened out 30 candidates from 4320 compound library with In Cell Interaction Trap method. The candidates were further confirmed and narrowed down to five compounds using the FRET method in a model cell. Among those five compounds, Acebutolol showed notable inhibition of JNK phosphorylation and elevation of glucose uptake in diabetic models of adipocyte and liver cell. Structural computation showed that the binding affinity of Acebutolol on the JNK-JIP1 interaction site was comparable to the known inhibitor, BI-78D3. Our results suggest that Acebutolol, an FDA-approved beta blocker for hypertension therapy, could have a new repurposed effect on type 2 diabetes elevating glucose uptake process by inhibiting JNK-JIP1 interaction.