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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.
Yarishkin, Oleg,Lee, Jaekwang,Jo, Seonmi,Hwang, Eun Mi,Lee, C. Justin The Korean Society for Brain and Neural Science 2015 Experimental Neurobiology Vol.24 No.3
<P>Like neurons, astrocytes produce and release GABA to influence neuronal signaling. At the perforant path to dentate gyrus granule neuron synapse, GABA from astrocyte was found to be a strong inhibitory factor, which impairs synaptic transmission, synaptic plasticity and memory in Alzheimer's disease. Although astrocytic GABA is observed in many brain regions, its physiological role has not been clearly demonstrated yet. Here, we show that astrocytic GABA exerts disinhibitory action to dentate granule neurons by targeting GABA<SUB>B</SUB> receptors of GABAergic interneurons in wild-type mice. This disinhibitory effect is specific to a low intensity of electrical stimulation at perforant path fibers. Inversely in Alzheimer's disease model mice, astrocytic GABA targets GABA<SUB>A</SUB> receptors and exerts inhibitory action by reducing release probability of glutamatergic perforant path terminals. These results suggest that astrocytic GABA differentially modulates the signaling from cortical input to dentate gyrus under physiological and pathological conditions.</P>
Oleg V. Yarishkin,Eun Mi Hwang,Donggyu Kim,Jae Cheal Yoo,Sang Soo Kang,Deok Ryoung Kim,Jae-Hee-Jung Shin,Hye-Joo Chung,Ho-Sang Jeong,Dawon Kang,Jaehee Han,Jae-Yong Park,Seong-Geun Hong 대한생리학회-대한약리학회 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 excitation- contraction (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 3ՌM, diclofenac inhibited reversibly the Na<sup>+</sup> current and did irreversibly the L-type Ca<sup>2+</sup> channels-mediated inward current (IC<sub>50</sub>=12.89±0.43ՌM) in a dose-dependent manner. However, nifedipine, a well-known L-type channel blocker, effectively inhibited the L-type Ca<sup>2+</sup> currents but not the Na<sup>+</sup> current. Our finding may explain that diclofenac causes the CV risk by the inhibition of L-type Ca<sup>2+</sup> channel, leading to the impairment of E-C coupling in cardiac myocytes.
GABA from reactive astrocytes impairs memory in mouse models of Alzheimer's disease
Jo, Seonmi,Yarishkin, Oleg,Hwang, Yu Jin,Chun, Ye Eun,Park, Mijeong,Woo, Dong Ho,Bae, Jin Young,Kim, Taekeun,Lee, Jaekwang,Chun, Heejung,Park, Hyun Jung,Lee, Da Yong,Hong, Jinpyo,Kim, Hye Yun,Oh, Soo- Nature Publishing Group, a division of Macmillan P 2014 Nature medicine Vol.20 No.8
In Alzheimer's disease (AD), memory impairment is the most prominent feature that afflicts patients and their families. Although reactive astrocytes have been observed around amyloid plaques since the disease was first described, their role in memory impairment has been poorly understood. Here, we show that reactive astrocytes aberrantly and abundantly produce the inhibitory gliotransmitter GABA by monoamine oxidase-B (Maob) and abnormally release GABA through the bestrophin 1 channel. In the dentate gyrus of mouse models of AD, the released GABA reduces spike probability of granule cells by acting on presynaptic GABA receptors. Suppressing GABA production or release from reactive astrocytes fully restores the impaired spike probability, synaptic plasticity, and learning and memory in the mice. In the postmortem brain of individuals with AD, astrocytic GABA and MAOB are significantly upregulated. We propose that selective inhibition of astrocytic GABA synthesis or release may serve as an effective therapeutic strategy for treating memory impairment in AD.
최재혁,Oleg Yarishkin,김은주,배연주,김아정,김승찬,유강현,조장훈,황은미,박재용 생화학분자생물학회 2018 Experimental and molecular medicine Vol.50 No.-
Two-pore domain K+ (K2P) channels have been shown to modulate neuronal excitability. The physiological role of TWIK-1, the first identified K2P channel, in neuronal cells is largely unknown, and we reported previously that TWIK-1 contributes to the intrinsic excitability of dentate gyrus granule cells (DGGCs) in mice. In the present study, we investigated the coexpression of TWIK-1 and TASK-3, another K2P member, in DGGCs. Immunohistochemical staining data showed that TASK-3 proteins were highly localized in the proximal dendrites and soma of DGGCs, and this localization is similar to the expression pattern of TWIK-1. TWIK-1 was shown to associate with TASK-3 in DGGCs of mouse hippocampus and when both genes were overexpressed in COS-7 cells. shRNA-mediated gene silencing demonstrated that TWIK-1/TASK-3 heterodimeric channels displayed outwardly rectifying currents and contributed to the intrinsic excitability of DGGCs. Neurotensin–neurotensin receptor 1 (NT–NTSR1) signaling triggered the depolarization of DGGCs by inhibiting TWIK-1/TASK-3 heterodimeric channels, causing facilitated excitation of DGGCs. Taken together, our study clearly showed that TWIK-1/TASK-3 heterodimeric channels contribute to the intrinsic excitability of DGGCs and that their activities are regulated by NT–NTSR1 signaling.
김동규,유재철,김은주,이영선,Oleg V. Yarishkin,이다용,이건호,홍성근,황은미,박재용 대한내분비학회 2014 Endocrinology and metabolism Vol.29 No.2
Background: Mitochondrial trans-2-enoyl-CoA reductase (MECR) is involved in mitochondrial synthesis of fatty acids and is highly expressed in mitochondria. MECR is also known as nuclear receptor binding factor-1, which was originally reported with yeast two-hybrid screening as a binding protein of the nuclear hormone receptor peroxisome proliferator-activated receptor α (PPARα). However, MECR and PPARα are localized at different compartment, mitochondria, and the nucleus, respectively. Therefore, the presence of a cytosolic or nuclear isoform of MECR is necessary for functional interaction between MECR and PPARα. Methods: To identify the expression pattern of MECR and the cytosolic form of MECR (cMECR), we performed reverse transcription polymerase chain reaction (RT-PCR) with various tissue samples from Sprague-Dawley rats. To confirm the interaction between cMECR and PPARα, we performed several binding assays such as yeast two-hybrid, coimmunoprecipitation, and bimolecular fluorescence complementation. To observe subcellular localization of these proteins, immunocytochemistry was performed. A luciferase assay was used to measure PPARα activity. Results: We provide evidence of an alternatively spliced variant of the rat MECR gene that yields cMECR. The cMECR lacks the N-terminal 76 amino acids of MECR and shows uniform distribution in the cytoplasm and nucleus of HeLa cells. cMECR directly bound PPARα in the nucleus and increased PPARα-dependent luciferase activity in HeLa cells. Conclusion: We found the cytosolic form of MECR (cMECR) was expressed in the cytosolic and/or nuclear region, directly binds with PPARα, and enhances PPARα activity.