• Genomics & Informatics
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• v.19 no.1
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• pp.9.1-9.5
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• 2021

Mammalian olfactory receptors are a family of G protein-coupled receptors (GPCRs) that occupy a large part of the genome. In human genes, olfactory receptors account for more than 40% of all GPCRs. Several types of GPCR structures have been identified, but there is no single olfactory receptor whose structure has been determined experimentally to date. The aim of this study was to model the interactions between an olfactory receptor and its ligands at the molecular level to provide hints on the binding modes between the OR2W1 olfactory receptor and its agonists and inverse agonists. The results demonstrated the modes of ligand binding in a three-dimensional model of OR2W1 and showed a statistically significant difference in binding affinity to the olfactory receptor between agonists and inverse agonists.

• Proceedings of the Korean Society of Life Science Conference
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• 2002.09a
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• pp.89-89
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• 2002

• The Korean Journal of Pain
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• v.9 no.2
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• pp.318-325
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• 1996

Background: Sympathectomy relieves pain in sympathectically maintained pain, and subcutaneous injection of norepinephrine(NE) can rekindle mechanical allodynia. However, the mechanism of rekindling is not clear. The purpose of this study is to investigate which subtype of $\alpha$-adrenoceptor is involved in NE-induced rekindling of mechanical allodynia in sympathectomized neuropathic rats. Methods: Neuropathic injury was produced by tightly ligating the left L5 and L6 spinal nerves of 36 male Sprague-Dawley rats and bilateral lumbar sympathectomy was done at two weeks postoperatively. Starting at 7 days after sympathectomy, rekindling of mechanical allodynia was induced by NE and clonidine injected into the left paw, which was reversed by pretreatment of phentolamine and idazoxan. Mechanical allocynia was quantified by measuring the frequency of foot lifts to two von Frey filaments applied to the paw. Results: All tested rats displayed well-developed signs of mechanical allodynia at the left paw that were abolished by a bilateral lumbar sympathectomy. Subcutaneous (s.c.) injection of NE (0.05 ${\mu}g$) into the affected paw of sympathectomized neuropathic rats rekindled previous mechanical allodynia. These effects could be mimicked by an ${\alpha}_2$-receptor agonist clonidine, but not by an ${\alpha}_1$-receptor agonist phenylephrine. The NE-induced rekindling of mechanical allodynia was significantly reduced by prior s.c. injection of a mixed $\alpha$-receptor antagonist phentolamine (20${\mu}g$) and ${\alpha}_2$-receptor antagonist idazoxan(20${\mu}g$), but not by a ${\alpha}_1$-receptor antagonist terazosin (20${\mu}g$). The pretreatment of idazoxan produced dose-related inhibition of NE-induced rekindling of mechanical allodynia. The rekindling induced by ${\alpha}_2$-receptor agonist clonidine (5${\mu}g$) was also reversed by prior s.c. injection of ${\alpha}_2$-receptor antagonist idazoxan (20${\mu}g$). Conclusion: Subcutaneous injection of NE into the paw of sympathectomized neuropathic rats rekindles mechanical allodynia, which is reversed by an ${\alpha}_2$-, but not by an ${\alpha}_1$-receptor antagonist. Therefore, rekindling of mechanical allodynia in sympathectomized neuropathic rats is mediated by ${\alpha}_2$-adrenoceptor.

• YAKHAK HOEJI
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• v.43 no.5
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• pp.642-651
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• 1999

Nonsedating antihistamines do net cause sedation in therapeutic doses because these drugs hardly cross the blood-brain barrier. Since most of the peripheral side dffects of conventional antihistamines are related to their muscarinic receptor blocking action, the present study was performed to investigate whether nonsedating antihistamines interact with the muscarinic receptors and discriminate the muscarinic receptor subtypes in the rat cerebral microsomal fraction which containes both $M_1,{\;}M_2,{\;}M_3{\;}and{\;}M_4$ receptors. Five nonsedating antihistamines at high concentrations inhibited [$^3H$]QNB binding to the muscarinic receptor in a dose-dependent manner. The inhibition curves of these drugs except loratadine which showed positive cooperativity (nH=1.55) were steep (nH=1), indicating interaction with a single homogenous population of the binding sites. Astemizole, clemizole and mequitazine increased the $K_D$ value for [$^3H$]QNB without affecting the binding site concentrations, and this increase in the $K_D$ value resulted from the ability of these drugs to slow [$^3H$]QNB-receptor association. The Ki values of astemizole, clemizole and mequitazine for the inhibition for the inhibition of [$^3H$]QNB binding to muscarinic receptor were 0.58, 5.99 and $0.007{\;}{\mu}M$, respectively. However, loratadine and terfenadine inhibited noncompetitively [$^3H$]QNB binding with the normalized $IC_50$ value of about $2{\;}{\mu}M$. These results demonstrate that; 1) astemizole, clemizole and mequitazine interact directly with the muscarinic receptor at high concentrations; 2) muscarinic receptor blocking potency of these drugs varies widely among drugs; 3) these drugs do not discriminate between muscarinic receptor subtypes.

• Bulletin of the Korean Chemical Society
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• v.35 no.5
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• pp.1365-1374
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• 2014

Thirteen analogs of tridecapeptide ${\alpha}$-factor (WHWLQLKPGQPMY) of Saccharomyces cerevisiae with C- or N-terminal Trp extension and isosteric replacement by Aib at position 8 and 11, Trp at position 13, D-Ala at position 9, and Orn and Glu at position 6 were synthesized and assayed for their biological activity. Receptor binding assay was carried out using our newly developed spectrophotometric method with detector peptide 14. C- or N-terminal extended analogs, ${\alpha}$-factor-$[Trp]_n$ (n =1-5) 1-5 and $[N-Trp]_1$-${\alpha}$-factor 6, were all less active than native ${\alpha}$-factor and gradual decreases in both activity and receptor affinity were observed with greater Trp extension. Trp-substituted analog at position 13, $[Trp^{13}]{\alpha}$-factor 7, exhibited about 2-fold reductions in both activity and receptor affinity. Aib-substituted analogs, $[Aib^8]{\alpha}$-factor 8 and $[Aib^{11}]{\alpha}$-factor 9, showed 5- to 10-fold reduction in activity as well as 3-fold reduction in receptor affinity compared to native ${\alpha}$-factor. $[Orn^6]{\alpha}$-factor 10 demonstrated strong potency with a 7.0-fold increase in halo activity as well as 1.8-fold increase in receptor affinity compared to native ${\alpha}$-factor. For two double substituted analogs, [$Glu^6,{\small{D}}-Ala^9$]${\alpha}$-factor 12 showed the slightly decreased potency in halo activity compared to analog 10, whereas [$Orn^6,{\small{D}}-Ala^9$]${\alpha}$-factor 11 exhibited 15-fold higher halo activity as well as nearly 3-fold higher receptor affinity compared to native ${\alpha}$-factor.

• Development and Reproduction
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• v.11 no.3
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• pp.179-185
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• 2007

The estrogens and estrogenic endocrine disrupting chemicals(EDCs) function through a steroid nuclear receptor-mediated process and subsequently regulate the transcription of mRNA for a number of target proteins. The estrogen receptor-related receptors(ERRs), which are structurally similar to estrogen receptors, are members of orphan nuclear receptor in the nuclear receptor superfamily and their functions are known to be involved in the formation of extra-embryonic ectoderm. To investigate effects of EDCs on early embryogenesis and ERR gene expression in marine invertebrates, we examined morphological changes and the mRNA expression of $ERR{\beta}$ like 1 in sea urchin Strongylocentrotus nudus exposed to estradiol-$17{\beta}(E_2)$ or nonylphenol(NP). The $E_2$ and NP-exposed embryos showed a delayed development compared to control embryos. Furthermore, they showed abnormal embryonic developments at late stages, i.e., blastular, gastrula and plutei stages. The mRNA level of $ERR{\beta}$ like 1 at the gastrula stage was significantly lower in $E_2$ and NP-exposed embryos than those of control group. These results suggest that NP and $E_2$ are potent chemicals causing abnormal embryonic development of S. nudus through at least in part down-regulated $ERR{\beta}$ like 1.

• Biomolecules & Therapeutics
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• v.19 no.1
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• pp.1-8
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• 2011

G-protein coupled receptors (GPCRs) constitute an important class of drug targets and are involved in every aspect of human physiology including sleep regulation, blood pressure, mood, food intake, perception of pain, control of cancer growth, and immune response. Radiometric assays have been the classic method used during the search for potential therapeutics acting at various GPCRs for most GPCR-based drug discovery research programs. An increasing number of diverse small molecules, together with novel GPCR targets identified from genomics efforts, necessitates the use of high-throughput assays with a good sensitivity and specificity. Currently, a wide array of high-throughput tools for research on GPCRs is available and can be used to study receptor-ligand interaction, receptor driven functional response, receptor-receptor interaction,and receptor internalization. Many of the assay technologies are based on luminescence or fluorescence and can be easily applied in cell based models to reduce gaps between in vitro and in vivo studies for drug discovery processes. Especially, cell based models for GPCR can be efficiently employed to deconvolute the integrated information concerning the ligand-receptor-function axis obtained from label-free detection technology. This review covers various platform technologies used for the research of GPCRs, concentrating on the principal, non-radiometric homogeneous assay technologies. As current technology is rapidly advancing, the combination of probe chemistry, optical instruments, and GPCR biology will provide us with many new technologies to apply in the future.

• Korean Journal of Biological Psychiatry
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• v.8 no.1
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• pp.106-110
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• 2001

Background : Dopamine receptors have been regarded as a strong candidate involved in etiology of schizophrenia and a target for various antipsychotic drugs. The purpose of our study was to investigate whether dopamine $D_1$ receptor(DRD1) gene polymorphisms would predict the treatment response to antipsychotics in schizophrenia. Method : One hundred thirty-four schizophrenic patients, who met DSM-IV criteria for schizophrenia were entered into a 48 -week study. The psychopathology of the patients was assessed at baseline, 12th, 24th 48th weeks of treatment by PANSS. Responders were defined by a 20% of the reduction in total PANSS score at end point. The genomic DNA fragment corresponding to nucleotides of dopamine $D_1$ receptor gene was amplified by polymerase chain reaction(PCR). Result: Neither allelic frequencies nor genotypes for dopamine $D_1$ receptor differed significantly between responders and non-responders. Also, there was no difference of changes of PANSS scores among three genotype groups of the dopamine $D_1$ receptor. Conclusion : Allelic variation in the dopamine $D_1$ gene is not associated with individual differences in antipsychotic response.

• BMB Reports
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• v.54 no.5
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• pp.272-277
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• 2021

RalBP1 associated EPS domain containing 1 (REPS1) is conserved from Drosophila to humans and implicated in the endocytic system. However, an exact role of REPS1 remains largely unknown. Here, we demonstrated that mitogen activated protein kinase kinase (MEK)-p90 ribosomal S6 Kinase (RSK) signaling pathway directly phosphorylated REPS1 at Ser709 upon stimulation by epidermal growth factor (EGF) and amino acid. While REPS2 is known to be involved in the endocytosis of EGF receptor (EGFR), REPS1 knockout (KO) cells did not show any defect in the endocytosis of EGFR. However, in the REPS1 KO cells and the KO cells reconstituted with a non-phosphorylatable REPS1 (REPS1 S709A), the recycling of transferrin receptor (TfR) was attenuated compared to the cells reconstituted with wild type REPS1. Collectively, we suggested that the phosphorylation of REPS1 at S709 by RSK may have a role of the trafficking of TfR.

• Archives of Pharmacal Research
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• v.19 no.5
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• pp.390-395
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• 1996

To investigate whether $AT_{1}$ receptor antagonists are acting by increasing endothelium-de-pendent and -independent relaxation of aortas in normotensive rats, $AT_{1}$ receptor antagonists, losartan and KR-30988, and angiotensin converting enzyme inhibitor, captopril, were orally administered for two weeks (50 mg/kg, b.i.d.). THe blood pressure, heart rate and body weight were not significantly changed by losartan, KR-30988 and captopril compared to the control group. In aortic preparations, the $pD_{2}$ of KR-30988 for ACh-induced relaxation was 8.33 $\pm$ 0.16, significantly (p <0.05) lower than that of control group $(7.71 \pm 0.15)$. ACh-induced relaxation was significantly increased on losartan-treated group (p<0.01) at $10^{-6}$ M of ACh, and in captopril-treated group (p<0.05) at the range of $10^{-7}$ -$10^{-5}$ M of ACh. The $pD_{2}$ values for histamine-induced relaxatio of losartan, KR-30988 and captopril were 5.57 $\pm$ 0.10, 5.85 $\pm$ 0.21 and 5.60 $\pm$ 0.01, respectively, with significant differences in all groups (p<0.01) compared to that of control group (5.13 $\pm$ 0.09). ACh-induced relaxations of aortic preparations were not changed by pretreatment of indomethacin ($10_{-5}$ M), and completely bolcked by pretreatment of L-NAME $(10_{-5}M)$ in all groups. Sodium nitroprusside-induced relaxations were not significantly changed by all drugs tested in this experiments. These results suggest that $AT_{1}$ receptor antagonists, losartan and KR-30988, enhance the endothelium-dependent relaxatio on aortic preparations through the release of, or increase sensitivity, to nitric oxide in nor-motensive rats.