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말초 및 중추신경계에서 칼슘채널 및 NMDA 매개 채널의 억제제로의 진세노사이드 Rg<sub>3</sub>의 효과
임혜원,Rhim, Hye-Whon 고려인삼학회 2003 Journal of Ginseng Research Vol.27 No.3
Alternative medicines such as herbal products are increasingly being used for preventive and therapeutic purposes. Ginseng is the best known and most popular herbal medicine used worldwide. In spite of some beneficial effects of ginseng on the nervous system, little scientific evidence shows at the cellular level. In the present study, I have examined the direct modulation of ginseng total saponins and individual ginsenosides on the activation of $Ca^{2+}$ channels and NMDA-gated channels in cultured rat dorsal root ganglion (DRG) and hippocampal neurons, respectively. In DRG neurons, application of ginseng total saponins suppressed high-voltage-activated $Ca^{2+}$ channel currents and ginsenoside Rg$_3$, among the 11 ginsenosides tested, produced the strongest inhibition on $Ca^{2+}$ channel currents. Occlusion experiments using selective $Ca^{2+}$ channel blockers revealed that ginsenoside Rg$_3$ could modulate L-, N-, and P/Q-type currents. In addition, ginsenoside Rg$_3$ also proved to be an active component of ginseng actions on NMDA receptors in cultured hippocampal neurons. Application of ginsenoside Rg$_3$ suppressed NMDA-induced [Ca$^{2+}$]$_{i}$ increase and -gated channels using fura-2-based digital imaging and patch-clamp techniques, respectively. These results suggest that the modulation of $Ca^{2+}$ channels and NMDA receptors by ginsenoside Rg$_3$ could be part of the pharmacological basis of ginseng actions in the peripheral and central nervous systems.ous systems.
쥐 - 뇌의 히스타민 - N - 메칠전달효소의 정제와 일반 특성 연구
임혜원,최명언 ( Hye Whon Rhim,Myung Un Choi ) 생화학분자생물학회 1989 BMB Reports Vol.22 No.4
Histamine-N-Methyltransferase (HMT: E.C. 2.1.1.8) was purified by the methods of ammonium sulfate fractionation, DEAE-cellulose chromatography, hydroxylapatite chromatography, and gel filtration on Sephadex G-75. Overall purification was 280-fold with a recovery of 8%. The activity of HMT was determined by radioisotopic method with [^(14)CH₃]S-adenosylmethionine(SAM). The labelled SAM was prepared by rat liver SAM synthetase with [^(14)CH₃]-methionine. The specific activity of prepared HMT was 3.9 nmol/min/㎎ protein at pH 8.5. The K_m values of histamine and SAM were 12μM and 40μM, respectively. It was also examined the effects of some modification reagents on the enzyme activity. p-Chloromercuribenzoate and N-ethylmaleimide inhibited the enzyme activity, while iodoacetic acid, iodoacetamide and succinic anhydride activated the enzyme activity.
Choi, Sun-Hye,Shin, Tae-Joon,Lee, Byung-Hwan,Chu, Dae-hyun,Choe, Han,Pyo, Mi-Kyung,Hwang, Sung-Hee,Kim, Bo-Ra,Lee, Sang-Mok,Lee, Jun-Ho,Kim, Dong-Hyun,Kim, Hyoung-Chun,Rhim, Hye-whon,Nah, Seung-Yeol Elsevier 2010 european journal of pharmacology Vol.637 No.1
<P><B>Abstract</B></P><P>The slowly activating delayed rectifier K<SUP>+</SUP> channels (<I>I</I><SUB><I>Ks</I></SUB>) are one of the main pharmacological targets for development of drugs against cardiovascular diseases. Cardiac <I>I</I><SUB><I>Ks</I></SUB> consists of KCNQ1 plus KCNE1 subunits. Ginsenoside, one of the active ingredient of <I>Panax ginseng</I>, enhances cardiac <I>I</I><SUB><I>Ks</I></SUB> currents. However, little is known about the molecular mechanisms of how ginsenoside interacts with channel proteins to enhance cardiac <I>I</I><SUB><I>Ks</I></SUB>. In the present study, we investigated ginsenoside Rg<SUB>3</SUB> (Rg<SUB>3</SUB>) effects on human <I>I</I><SUB><I>Ks</I></SUB> by co-expressing human KCNQ1 plus KCNE1 subunits in <I>Xenopus</I> oocytes. Rg<SUB>3</SUB> enhanced <I>I</I><SUB><I>Ks</I></SUB> currents in concentration- and voltage-dependent manners. The EC<SUB>50</SUB> was 15.2±8.7µM. However, in oocytes expressing KCNQ1 alone, Rg<SUB>3</SUB> inhibited the currents with concentration- and voltage-dependent manners. The IC<SUB>50</SUB> was 4.8±0.6µM. Since Rg<SUB>3</SUB> acts opposite ways in oocytes expressing KCNQ1 alone or KCNQ1 plus KCNE1 subunits, we examined Rg<SUB>3</SUB> effects after co-expression of different ratios of KCNE1 and KCNQ1. The increase of KCNE1/KCNQ1 ratio converted <I>I</I><SUB><I>Ks</I></SUB> inhibition to <I>I</I><SUB><I>Ks</I></SUB> activations. One to ten ratio of KCNE1 and KCNQ1 subunit is required for Rg<SUB>3</SUB> activation of <I>I</I><SUB><I>Ks</I></SUB>. Mutations of K318 and V319 into K318Y and V319Y of KCNQ1 channel abolished Rg<SUB>3</SUB> effects on KCNQ1 or KCNQ1 plus KCNE1 channel currents. The docked modeling revealed that K318 residue plays a key role in stabilization between Rg<SUB>3</SUB> and KCNQ1 plus KCNE1 or KCNQ1 subunit. These results indicate that Rg<SUB>3</SUB>-induced activation of <I>I</I><SUB><I>Ks</I></SUB> requires co-assembly of KCNQ1 and KCNE1 subunits and achieves this through interaction with residues K318 and V319 of KCNQ1 subunit.</P>
Purification and General Characterization of Rat Brain Histamine-N-Methyltransferase
임혜원,최명언,Rhim, Hye-Whon,Choi, Myung-Un 생화학분자생물학회 1989 한국생화학회지 Vol.22 No.4
쥐 뇌의 histamine N-methyltransferase(HMT)는 $(NH_4)_2SO_4$ 분류법, DEAE-셀루로즈 크로마토그래피, hydroxylapatite 크로마토그래피와 Sephadex G-75에 대한 젤 여과법으로 정제되었다. 전체 정제는 8%의 회수율로 280배 정제되었다. HMT 활성도는 $[^{14}CH_3]$-S-adenosylmethionine(SAM)에 의한 방사성 동위원소법으로 결정하였다. 방사성 SAM은 $[^{14}CH_3]$ methionine을 가지고 쥐 간의 SAM synthetase에 의하여 합성하였다. 준비된 HMT의 specific actitity는 pH8.5에서 3.9nmol/min/mg protein이다. Histamine과 SAM에 대한 $K_m$값은 각각 $12{\mu}M$과 $40{\mu}M$이다. 효소활성에 대한 몇 가지의 변형시약을 검토했을 때 p-chloromercuribenzoate와 N-ethyl maleimide는 활성도를 감소시켰고 iodoacetic acid, iodoacetamide와 succinic anhydride는 효소의 활성도를 증가시킴이 관찰되었다. Histamine-N-Methyltransferase (HMT: E.C. 2.1.1.8) was purified by the methods of ammonium sulfate fractionation, DEAE-cellulose chromatography, hydroxylapatite chromatography, and gel filtration on Sephadex G-75. Overall purification was 280-fold with a recovery of 8%. The activity of HMT was determined by radioisotopic method with $[^{14}CH_3]$S-adenosylmethionine(SAM). The labelled SAM was prepared by rat liver SAM synthetase with $[^{14}CH_3]$-methionine. The specific activity of prepared HMT was 3.9 nmol/min/mg protein at pH 8.5. The $K_m$ values of histamine and SAM were $12{\mu}M$ and $40{\mu}M$, respectively. It was also examined the effects of some modification reagents on the enzyme activity. p-Chloromercuribenzoate and N-ethylmaleimide inhibited the enzyme activity, while iodoacetic acid, iodoacetamide and succinic anhydride activated the enzyme activity.
효소를 이용한 방사성 표지 s - Adenoxsyl - L - [ methyl - 14C ] methionine 의 생산
임혜원,박인원,최명언 ( Hye Whon Rhim,In Won Park,Myung Un Choi ) 생화학분자생물학회 1991 BMB Reports Vol.24 No.5
S-Adenosylmethionine (SAM) serves as the major methyl group donor in biological system. This study describes an upgrade method for radiolabelled biosynthesis of SAM by methionine adenosyltransferase (MAT) in the presence of ATP and L-[^(14)C-methyl]methionine. The MAT was partially purified from rat liver and reoptimized the assay condition. The final yield of biosynthesis was better than 90% with relatively high specific radioactivity.
Enzymatic Preparation of Radiolabelled S-Adenosyl-L-$[methyl-^{14}C]$ methionine
임혜원,박인원,최명언,Rhim, Hye-Whon,Park, In-Won,Choi, Myung-Un 생화학분자생물학회 1991 한국생화학회지 Vol.24 No.5
S-Adenosylmethionine (SAM)은 생체계에서 주요 메칠기 주게로 사용된다. 이 연구는 L-$[^{14}C-methyl]$methionine과 ATP 존재하에서 methionine adenosyltransferase (MAT)을 이용하여 방사성 표지된 SAM의 생합성 방법을 설명한다. MAT는 쥐 간으로부터 부분정제 하였으며 그 활동도의 최적조건을 재조절하였다. 생성률을 90% 이상이었고 비교적 높은 비방사성이 얻어졌다. S-Adenosylmethionine (SAM) serves as the major methyl group donor in biological system. This study describes an upgrade method for radiolabelled biosynthesis of SAM by methionine adenosyltransferase (MAT) in the presence of ATP and L-$[^{14}C-methyl]$methionine. The MAT was partially purified from rat liver and reoptimized the assay condition. The final yield of biosynthesis was better than 90% with relatively high specific radioactivity.
Ginsenosides Inhibit NMDA Receptor-Mediated Epileptic Discharges in Cultured Hippocampal Neurons
Kim, Sun-Oh,Rhim, Hye-Whon The Pharmaceutical Society of Korea 2004 Archives of Pharmacal Research Vol.27 No.5
Epilepsy or the occurrence of spontaneous recurrent epileptiform discharges (SREDs, seizures) is one of the most common neurological disorders. Shift in the balance of brain between excitatory and inhibitory functions due to different types of structural or functional alterations may cause epileptiform discharges. N-Methyl-D-aspartate (NMDA) receptor dysfunctions have been implicated in modulating seizure activities. Seizures and epilepsy are clearly dependent on elevated intracellular calcium concentration ([C $a^{2+}$]$_{i}$ ) by NMDA receptor activation and can be prevented by NMDA antagonists. This perturbed [C $a^{2+}$]$_{i}$ levels is forerunner of neuronal death. However, therapeutic tools of elevated [C $a^{2+}$]$_{i}$ level during status epilepticus (SE) and SREDs have not been discovered yet. Our previous study showed fast inhibition of ginseng total saponins and ginsenoside R $g_3$ on NMDA receptor-mediated [C $a^{2+}$]$_{i}$ in cultured hippocampal neurons. We, therefore, examined the direct modulation of ginseng on hippocampal neuronal culture model of epilepsy using fura-2-based digital $Ca^{2+}$ imaging and neuronal viability assays. We found that ginseng total saponins and ginsenoside R $g_3$ inhibited $Mg^{2+}$ free-induced increase of [C $a^{2+}$]$_{i}$ and spontaneous [C $a^{2+}$]$_{i}$ oscillations in cultured rat hippocampal neurons. These results suggest that ginseng may playa neuroprotective role in perturbed homeostasis of [C $a^{2+}$]$_{i}$ and neuronal cell death via the inhibition of NMDA receptor-induced SE or SREDs.d SE or SREDs..
Lee, Byung-Hwan,Choi, In-Sung,Rhim, Hye-Whon,Choi, Kyung-Il,Nah, Seung-Yeol,Nam, Ghil-Soo Korean Chemical Society 2009 Bulletin of the Korean Chemical Society Vol.30 No.11
5-$HT_{3}$ receptor;5-$HT_{3A}$ receptor channel activity;Novel 5-$HT_{3}$ receptor channel current blockers;Chlorophenyl substituted piperazinylethylaminomethylpyrazoles; The 5-$HT_{3A}$ receptors are one of ligand-gated ion channels and are known to be involved in visceral pain, anxiety, or anticancer agent-induced nausea and vomiting. In present study, we designed novel skeletons based on the developed 5-$HT_{3}$ receptor antagonists and evaluated their effects on 5-$HT_{3A}$ receptor channel currents ($I_{5-HT}$) of a series of pyrazole derivatives having N-chlorophenylpiperazine functionality (6-9). We found that most of N-p-chlorophenyl substituted piperazinyl-pyrazole derivatives (7b, 7c, 7e and 7h) exhibited the high potency for the inhibition of $I_{5-HT}$, whereas the compound without chloride (6) or with m-chlorophenyl group (a serious of 8 and 9) showed the low potency. These result indicate that p-chlorophenyl group is might play an important role for increasing the inhibitory potency on $I_{5-HT}$.