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Featured researches published by Han Choe.


Journal of Biological Chemistry | 2015

Ligand binding pocket formed by evolutionarily conserved residues in the glucagon-like peptide-1 (GLP-1) receptor core domain

Mi Jin Moon; Yoo Na Lee; Sumi Park; Arfaxad Reyes-Alcaraz; Jong Ik Hwang; Robert P. Millar; Han Choe; Jae Young Seong

Background: Little is known about the interaction between GLP-1 and the heptahelical core domain of GLP1R. Results: GLP-1 Asp9 and Gly4 interact with the evolutionarily conserved residues in extracellular loop 3. Conclusion: Ligand binding pocket formed by evolutionarily conserved residues in the GLP1R core domain. Significance: This study highlights the mechanism underlying high affinity interaction between GLP-1 and the binding pocket of the receptor. Glucagon-like peptide-1 (GLP-1) plays a pivotal role in glucose homeostasis through its receptor GLP1R. Due to its multiple beneficial effects, GLP-1 has gained great attention for treatment of type 2 diabetes and obesity. However, little is known about the molecular mechanism underlying the interaction of GLP-1 with the heptahelical core domain of GLP1R conferring high affinity ligand binding and ligand-induced receptor activation. Here, using chimeric and point-mutated GLP1R, we determined that the evolutionarily conserved amino acid residue Arg380 flanked by hydrophobic Leu379 and Phe381 in extracellular loop 3 (ECL3) may have an interaction with Asp9 and Gly4 of the GLP-1 peptide. The molecular modeling study showed that Ile196 at transmembrane helix 2, Met233 at ECL1, and Asn302 at ECL2 of GLP1R have contacts with His1 and Thr7 of GLP-1. This study may shed light on the mechanism underlying high affinity interaction between the ligand and the binding pocket that is formed by these conserved residues in the GLP1R core domain.


Journal of Biological Chemistry | 2008

Identification of Farnesyl Pyrophosphate and N-Arachidonylglycine as Endogenous Ligands for GPR92

Da Young Oh; Jung Min Yoon; Mi Jin Moon; Jong-Ik Hwang; Han Choe; Ju Yeon Lee; Jae Il Kim; Sunoh Kim; Hyewhon Rhim; David K. O'Dell; J. Michael Walker; Heung Sik Na; Min Goo Lee; Hyuk Bang Kwon; Kyungjin Kim; Jae Young Seong

A series of small compounds acting at the orphan G protein-coupled receptor GPR92 were screened using a signaling pathway-specific reporter assay system. Lipid-derived molecules including farnesyl pyrophosphate (FPP), N-arachidonylglycine (NAG), and lysophosphatidic acid were found to activate GPR92. FPP and lysophosphatidic acid were able to activate both Gq/11- and Gs-mediated signaling pathways, whereas NAG activated only the Gq/11-mediated signaling pathway. Computer-simulated modeling combined with site-directed mutagenesis of GPR92 indicated that Thr97, Gly98, Phe101, and Arg267 of GPR92 are responsible for the interaction of GPR92 with FPP and NAG. Reverse transcription-PCR analysis revealed that GPR92 mRNA is highly expressed in the dorsal root ganglia (DRG) but faint in other brain regions. Peripheral tissues including, spleen, stomach, small intestine, and kidney also expressed GPR92 mRNA. Immunohistochemical analysis revealed that GPR92 is largely co-localized with TRPV1, a nonspecific cation channel that responds to noxious heat, in mouse and human DRG. FPP and NAG increased intracellular Ca2+ levels in cultured DRG neurons. These results suggest that FPP and NAG play a role in the sensory nervous system through activation of GPR92.


Journal of Biological Chemistry | 2012

Selective Gαi Subunits as Novel Direct Activators of Transient Receptor Potential Canonical (TRPC)4 and TRPC5 Channels

Jae-Pyo Jeon; Chansik Hong; Eun Jung Park; Ju-Hong Jeon; Nam-Hyuk Cho; In-Gyu Kim; Han Choe; Shmuel Muallem; Hyun Jin Kim; Insuk So

Background: Activation of TRPC4/5 channels is mediated by GPCR activation. Results: TRPC4/5 was activated by the Gαi/o-coupled receptor and the Gαi protein, which interacted directly with each other. Conclusion: Gαi proteins play an essential role as novel activators of TRPC4/5. Significance: Our findings provide new insights into the activation mechanism of inhibitory Gα proteins. The ubiquitous transient receptor potential canonical (TRPC) channels function as non-selective, Ca2+-permeable channels and mediate numerous cellular functions. It is commonly assumed that TRPC channels are activated by stimulation of Gαq-PLC-coupled receptors. However, whether the Gαq-PLC pathway is the main regulator of TRPC4/5 channels and how other Gα proteins may regulate these channels are poorly understood. We previously reported that TRPC4/TRPC5 can be activated by Gαi. In the current work, we found that Gαi subunits, rather than Gαq, are the primary and direct activators of TRPC4 and TRPC5. We report a novel molecular mechanism in which TRPC4 is activated by several Gαi subunits, most prominently by Gαi2, and TRPC5 is activated primarily by Gαi3. Activation of Gαi by the muscarinic M2 receptors or expression of the constitutively active Gαi mutants equally and fully activates the channels. Moreover, both TRPC4 and TRPC5 are activated by direct interaction of their conserved C-terminal SESTD (SEC14-like and spectrin-type domains) with the Gαi subunits. Two amino acids (lysine 715 and arginine 716) of the TRPC4 C terminus were identified by structural modeling as mediating the interaction with Gαi2. These findings indicate an essential role of Gαi proteins as novel activators for TRPC4/5 and reveal the molecular mechanism by which G-proteins activate the channels.


British Journal of Pharmacology | 2009

Blockade of HERG human K+ channels and IKr of guinea-pig cardiomyocytes by the antipsychotic drug clozapine

So-Young Lee; Young Jin Kim; Kyong-Tai Kim; Han Choe; Su-Hyun Jo

1 Clozapine, a commonly used antipsychotic drug, can induce QT prolongation, which may lead to torsades de pointes and sudden death. To investigate the arrhythmogenic side effects of clozapine, we studied the impact of clozapine on human ether‐a‐go‐go‐related gene (HERG) channels expressed in Xenopus oocytes and HEK293 cells, and on the delayed rectifier K+ currents of guinea‐pig cardiomyocytes. 2 Clozapine dose‐dependently decreased the amplitudes of the currents at the end of voltage steps, and the tail currents of HERG. The IC50 for the clozapine blockade of HERG currents in Xenopus oocytes progressively decreased relative to depolarization (39.9 μM at −40 mV, 28.3 μM at 0 mV and 22.9 μM at +40 mV), whereas the IC50 for the clozapine‐induced blockade of HERG currents in HEK293 cells at 36°C was 2.5 μM at +20 mV. 3 The clozapine‐induced blockade of HERG currents was time dependent: the fractional current was 0.903 of the control at the beginning of the pulse, but declined to 0.412 after 4 s at a test potential of 0 mV. 4 The clozapine‐induced blockade of HERG currents was use‐dependent, exhibiting more rapid onset and greater steady state blockade at higher frequencies of activation, with a partial relief of blockade observed when the frequency of activation was decreased. 5 In guinea‐pig ventricular myocytes held at 36°C, treatment with 1 and 5 μM clozapine blocked the rapidly activating delayed rectifier K+ current (IKr) by 24.7 and 79.6%, respectively, but did not significantly block the slowly activating delayed rectifier K+ current (IKs). 6 Our findings collectively suggest that blockade of HERG currents and IKr, but not IKs, may contribute to the arrhythmogenic side effects of clozapine.


Journal of Neuroscience Research | 2008

Okadaic acid increases autophagosomes in rat neurons: implications for Alzheimer's disease.

Seung Yong Yoon; Jung Eun Choi; Hee-Seok Kweon; Han Choe; Seong Who Kim; Onyou Hwang; Heuiran Lee; Joo-Yong Lee; Dong Hou Kim

Autophagosomes are accumulated in Alzheimers disease (AD), but the regulatory pathway of autophagy in AD remains largely unknown. By using electron microscopy, Western blotting, and immunocytochemistry, here we show that autophagosomes are accumulated in rat neurons by okadaic acid (OA), a protein phosphatase‐2A inhibitor known to enhance tau phosphorylation, β‐amyloid (Aβ) deposition, and neuronal death, which are the pathological hallmarks of AD. Autophagy can be generally induced via several distinct pathways, such as inhibition of mTOR or activation of beclin‐1. Interestingly, OA increased both mTOR and beclin‐1 pathways simultaneously, which suggests that autophagy in OA‐treated neurons is induced mainly via the beclin‐1 pathway, and less so via mTOR inhibition. Finally, inhibition of autophagy by 3MA reduced cytotoxicity in OA‐treated neurons. Our novel findings provide new insights into the pathology of and therapeutic intervention for AD.


Pharmacological Research | 2009

H1 antihistamine drug promethazine directly blocks hERG K+ channel

Su-Hyun Jo; Hee-Kyung Hong; Seon Ha Chong; Hui Sun Lee; Han Choe

Promethazine is a phenothiazine derivative with antihistaminic (H(1)), sedative, antiemetic, anticholinergic, and antimotion sickness properties that can induce QT prolongation, which may lead to torsades de pointes. Since block of cardiac human ether-a-go-go-related gene (hERG) channels is one of the leading causes of acquired long QT syndrome, we investigated the acute effects of promethazine on hERG channels to determine the electrophysiological basis for its proarrhythmic potential. Promethazine increased the action potential duration at 90% of repolarization (APD(90)) in a concentration-dependent manner, with an IC(50) of 0.73microM when action potentials were elicited under current clamp in guinea pig ventricular myocytes. We examined the effects of promethazine on the hERG channels expressed in Xenopus oocytes and HEK293 cells using two-microelectrode voltage-clamp and patch-clamp techniques. Promethazine induced a concentration-dependent decrease of the current amplitude at the end of the voltage steps and hERG tail currents. The IC(50) of promethazine dependent hERG block in Xenopus oocytes decreased progressively relative to the degree of depolarization. The IC(50) for the promethazine-induced block of the hERG currents in HEK293 cells at 36 degrees C was 1.46microM at +20mV. Promethazine affected the channels in the activated and inactivated states but not in the closed states. The S6 domain mutations, Y652A and F656A partially attenuated (Y652A) or abolished (F656A) the hERG current block. These results suggest that promethazine is a blocker of the hERG channels, providing a molecular mechanism for the arrhythmogenic side effects during the clinical administration of promethazine.


Experimental and Molecular Medicine | 2006

Implication of phosphorylation of the myosin II regulatory light chain in insulin-stimulated GLUT4 translocation in 3T3-F442A adipocytes.

Young Ok Choi; Hee Jeong Ryu; Hye_Rim Kim; Young Sook Song; Cheonghwan Kim; Wan Lee; Han Choe; Chae Hun Leem; Yeon Jin Jang

In adipocytes, insulin stimulates glucose transport primarily by promoting the translocation of GLUT4 to the plasma membrane. Requirements for Ca2+/ calmodulin during insulin-stimulated GLUT4 translocation have been demonstrated; however, the mechanism of action of Ca2+ in this process is unknown. Recently, myosin II, whose function in non-muscle cells is primarily regulated by phosphorylation of its regulatory light chain by the Ca2+/calmodulin-dependent myosin light chain kinase (MLCK), was implicated in insulin-stimulated GLUT4 translocation. The present studies in 3T3- F442A adipocytes demonstrate the novel finding that insulin significantly increases phosphorylation of the myosin II RLC in a Ca2+-dependent manner. In addition, ML-7, a selective inhibitor of MLCK, as well as inhibitors of myosin II, such as blebbistatin and 2,3-butanedione monoxime, block insulin- stimulated GLUT4 translocation and subsequent glucose transport. Our studies suggest that MLCK may be a regulatory target of Ca2+/calmodulin and may play an important role in insulin-stimulated glucose transport in adipocytes.


FEBS Letters | 2003

Activation in isolation: Exposure of the actin-binding site in the C-terminal half of gelsolin does not require actin

Kartik Narayan; Sakesit Chumnarnsilpa; Han Choe; Edward Irobi; Dunja Urosev; Uno Lindberg; Clarence E. Schutt; Leslie D. Burtnick; Robert Robinson

Gelsolin requires activation to carry out its severing and capping activities on F‐actin. Here, we present the structure of the isolated C‐terminal half of gelsolin (G4–G6) at 2.0 Å resolution in the presence of Ca2+ ions. This structure completes a triptych of the states of activation of G4–G6 that illuminates its role in the function of gelsolin. Activated G4–G6 displays an open conformation, with the actin‐binding site on G4 fully exposed and all three type‐2 Ca2+ sites occupied. Neither actin nor the type‐l Ca2+, which normally is sandwiched between actin and G4, is required to achieve this conformation.


European Journal of Pharmacology | 2008

Clomipramine block of the hERG K+ channel: accessibility to F656 and Y652.

Su-Hyun Jo; Hee-Kyung Hong; Seon Ha Chong; Kwang Hee Won; Sung Jun Jung; Han Choe

Clomipramine is a tricyclic antidepressant for psychiatric disorders that can induce QT prolongation, which may lead to torsades de pointes. Since blockade of cardiac human ether-a-go-go-related gene (hERG) channels is an important cause of acquired long QT syndrome, we investigated the acute effects of clomipramine on hERG channels to determine the electrophysiological basis for its proarrhythmic potential. We examined the effects of clomipramine on the hERG channels expressed in Xenopus oocytes and HEK293 cells using two-microelectrode voltage-clamp and patch-clamp techniques. Clomipramine induced a concentration-dependent decrease in the current amplitude at the end of the voltage steps and hERG tail currents. The IC50 for clomipramine needed to block the hERG current in Xenopus oocytes decreased progressively relative to the degree of depolarization. The fractional electrical distance was estimated to be delta=0.83. The IC50 for the clomipramine-induced blockade of the hERG currents in HEK293 cells at 36 degrees C was 0.13 microM at +20 mV. Clomipramine affected the channels in the activated and inactivated states but not in the closed states. The clomipramine-induced blockade of hERG was found to be use-dependent, exhibiting a more rapid onset and a greater steady-state block at the higher frequencies of activation. The S6 domain mutations, Y652A and F656A partially attenuated (Y652A) or abolished (F656A) the hERG-current blockade. These results suggest that clomipramine is a blocker of the hERG channels, providing a molecular mechanism for the arrhythmogenic side effects during the clinical administration of clomipramine.


Molecular Pharmacology | 2007

Ginsenoside Rg3 Inhibits Human Kv1.4 Channel Currents by Interacting with the Lys531 Residue

Jun-Ho Lee; Byung-Hwan Lee; Sun-Hye Choi; In-Soo Yoon; Mi Kyung Pyo; Tea-Joon Shin; Woo-Sung Choi; Yoongho Lim; Hyewhom Rhim; Kwang Hee Won; Young Whan Lim; Han Choe; Dong-Hyun Kim; Yang In Kim; Seung-Yeol Nah

We have demonstrated previously that the 20(S) but not the 20(R) form of ginsenoside Rg3 inhibited K+ currents flowing through Kv1.4 (hKv1.4) channels expressed in Xenopus laevis oocytes, pointing to the presence of specific interaction site(s) for Rg3 in the hKv1.4 channel. In the current study, we sought to identify this site(s). To this end, we first assessed how point mutations of various amino acid residues of the hKv1.4 channel affected inhibition by 20(S)-ginsenoside Rg3 (Rg3). Lys531 residue is known to be a key site for K+ activation and to be part of the extracellular tetraethylammonium (TEA) binding site; the mutation K531Y abolished the Rg3 effect and made the Kv1.4 channel sensitive to TEA applied to the extracellular side of the membrane. Mutations of many other residues, including the pH sensitive-site (H507Q), were without any significant effect. We next examined whether K+ and TEA could alter the effect of Rg3 and vice versa. We found that 1) raising [K+]o reduced the inhibitory effect of Rg3 on hKv1.4 channel currents, whereas Rg3 shifted the K+ activation curve to the right, and 2) TEA caused a rightward shift of the Rg3 concentration-response curve of wild-type hKv1.4 channel currents, whereas Rg3 caused a rightward shift of the TEA concentration-response curve of K531Y mutant channel currents. The docked modeling revealed that Lys531 plays a key role in forming hydrogen bonds between Rg3 and hKv1.4 channels. These results indicate that Rg3 inhibits the hKv1.4 channel current by interacting with residue Lys531.

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Su-Hyun Jo

Kangwon National University

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