• Biomolecules & Therapeutics
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• 제19권4호
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• pp.390-397
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• 2011

G protein-coupled receptor kinases (GRKs) and ${\beta}$-arrestins have been known as regulators of G protein-coupled receptors. However, it has been recently reported that GRKs and ${\beta}$-arrestins mediate receptor-mediated cellular responses in a G proteinin-dependent manner. In this scheme, GRKs work as a mediator or a scaffold protein. Among 7 members of the GRK family (GRK1-GRK7), GRK2 is the most extensively studied in vitro and in vivo. GRK2 is involved in cellular migration, insulin signaling, and cardiovascular disease. GRK6 in concert with ${\beta}$-arrestin 2 mediates chemoattractant-stimulated chemotaxis of T and B lymphocytes. GRK5 shuttles between the cytosol and nucleus, and regulates the activities of transcription factors. GRK3 and GRK4 do not seem to have striking effects on cellular responses other than receptor regulation. GRK1 and GRK7 play specific roles in regulation of rhodopsin function. In this review, these newly discovered functions of GRKs are briefly described.

• Biomolecules & Therapeutics
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• 제28권5호
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• pp.482-489
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• 2020

G protein-coupled receptor kinase 5 (GRK5) has been considered as a potential target for the treatment of heart failure as it has been reported to be an important regulator of pathological cardiac hypertrophy. To discover novel scaffolds that selectively inhibit GRK5, we have identified a novel small molecule inhibitor of GRK5, KR-39038 [7-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-2-(2-chlorophenyl)-6-fluoroquinazolin-4(3H)-one]. KR-39038 exhibited potent inhibitory activity (IC₅₀ value=0.02 µM) against GRK5 and significantly inhibited angiotensin II-induced cellular hypertrophy and HDAC5 phosphorylation in neonatal cardiomyocytes. In the pressure overload-induced cardiac hypertrophy mouse model, the daily oral administration of KR-39038 (30 mg/kg) for 14 days showed a 43% reduction in the left ventricular weight. Besides, KR-39038 treatment (10 and 30 mg/kg/day, p.o.) showed significant preservation of cardiac function and attenuation of myocardial remodeling in a rat model of chronic heart failure following coronary artery ligation. These results suggest that potent GRK5 inhibitor could effectively attenuate both cardiac hypertrophy and dysfunction in experimental heart failure, and KR-39038 may be useful as an effective GRK5 inhibitor for pharmaceutical applications.

• 대한약학회:학술대회논문집
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• 대한약학회 2003년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2-2
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• pp.77.2-77.2
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• 2003

The dopamine D2 receptor (D$_2$R) is target for antipsychotic drugs and associated with several neuropsychiatric disorders. The internalization (sequestration) of G protin-coupled receptor is caused by agonist-induced receptor phosphorylation mediated by GRK, followed by the interaction with ${\beta}$-arrestin. In this study, we examined the agonist-dependent sequestration/internalization of dopamine D$_2$R, which were transiently expressed in HEK 293 cells with of without GRK co-expression. Co-expression of GRK2 or GRK3 markedly enhanced the sequestration of D$_2$R. (omitted)

• Biomolecules & Therapeutics
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• 제27권4호
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• pp.414-422
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• 2019

There is accumulating evidence that microRNAs are emerging as pivotal regulators in the development and progression of neuropathic pain. MicroRNA-15a/16 (miR-15a/16) have been reported to play an important role in various diseases and inflammation response processes. However, whether miR-15a/16 participates in the regulation of neuroinflammation and neuropathic pain development remains unknown. In this study, we established a mouse model of neuropathic pain by chronic constriction injury (CCI) of the sciatic nerves. Our results showed that both miR-15a and miR-16 expression was significantly upregulated in the spinal cord of CCI rats. Downregulation of the expression of miR-15a and miR-16 by intrathecal injection of a specific inhibitor significantly attenuated the mechanical allodynia and thermal hyperalgesia of CCI rats. Furthermore, inhibition of miR-15a and miR-16 downregulated the expression of interleukin-$1{\beta}$ and tumor-necrosis factor-${\alpha}$ in the spinal cord of CCI rats. Bioinformatic analysis predicted that G protein-coupled receptor kinase 2 (GRK2), an important regulator in neuropathic pain and inflammation, was a potential target gene of miR-15a and miR-16. Inhibition of miR-15a and miR-16 markedly increased the expression of GRK2 while downregulating the activation of p38 mitogen-activated protein kinase and $NF-{\kappa}B$ in CCI rats. Notably, the silencing of GRK2 significantly reversed the inhibitory effects of miR-15a/16 inhibition in neuropathic pain. In conclusion, our results suggest that inhibition of miR-15a/16 expression alleviates neuropathic pain development by targeting GRK2. These findings provide novel insights into the molecular pathogenesis of neuropathic pain and suggest potential therapeutic targets for preventing neuropathic pain development.

• 한국식품영양과학회지
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• 제43권11호
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• pp.1674-1680
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• 2014

잡곡밥 메탄올 추출물이 가지는 산화적 스트레스 개선 효과를 확인하기 위하여 $H_2O_2$로 유도된 산화적 스트레스에 대한 LLC-PK1 세포의 보호 효과를 조사하였다. $250{\mu}M$의 $H_2O_2$에 의한 산화적 스트레스가 유발된 LLC-PK1 세포에 시료추출물을 처리한 결과, WR, TMR, GR 순으로 $H_2O_2$ 처리군에 비해 세포 생존율이 증가하였다(P<0.05). 특히 GRS와 GRK에서 정상군에 가까운 세포 생존율을 나타내어 $H_2O_2$에 의한 산화적 스트레스로 유발된 세포 손상에 대한 잡곡밥 추출물의 보호 효과를 확인할 수 있었다. 세포 내 활성산소(ROS)의 수준과 세포 내 지질과산화물질(MDA)의 생성 억제 효과 역시 WR, TMR, GR, GRK, GRS 순으로 증가하는 것을 관찰하였다. $H_2O_2$로 인하여 세포 내 항산화 효소인 SOD, CAT와 GSH-px 등의 활성이 감소된 LLC-PK1 세포에 잡곡밥 추출물을 처리했을 때 이들 효소의 활성이 증가했으며 특히 GRK, GRS군에서 현저하게 증가되었다. LLC-PK1 세포에서 $H_2O_2$에 의해 발생하는 산화적 스트레스에 대한 보호 효과를 측정한 결과 잡곡밥 추출물은 세포 손상을 억제하고 세포 내 활성산소(ROS)의 수준과 지질과산화물질(MDA)의 생성을 억제하며, 세포 내 항산화 효소의 활성을 증가시키는 효과를 가지는 것으로 보인다. 또한 항산화 효소유전자 발현에서도 위와 비슷한 효과를 나타내었다. 이상의 결과로 잡곡밥 메탄올 추출물, 특히 기능성 물질인 카레가루와 상황버섯 추출물이 첨가된 잡곡밥은 LLC-PK1 세포에 대한 보호 작용과 in vitro에서의 항산화 효과가 높은 것으로 확인되었다.

• Journal of Nutrition and Health
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• 제50권3호
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• pp.217-224
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• 2017

Purpose: Although it is well known thatmortality and morbidity due to cardiovascular diseases are higher in salt-sensitive subjects than in salt-resistant subjects, their underlying mechanisms related to obesity remain unclear. Here, we focused on salt-sensitive gene variants unrelated to monogenic obesity that interacted with sodium intake in humans. Methods: This review was written based on the modified $3^rd$ step of Khans' systematic review. Instead of the literature, subject genes were based on candidate genes screened from our preliminary Genome-Wide Association Study (GWAS). Finally, literature related to five genes strongly associated with salt sensitivity were analyzed to elucidate the mechanism of obesity. Results: Salt sensitivity is a measure of how blood pressure responds to salt intake, and people are either salt-sensitive or salt-resistant. Otherwise, dietary sodium restriction may not be beneficial for everyone since salt sensitivity may be associated with inherited susceptibility. According to our previous GWAS studies, 10 candidate genes and 11 single nucleotide polymorphisms (SNPs) associated with salt sensitivity were suggested, including angiotensin converting enzyme (ACE), ${\alpha}$-adducin1 (ADD1), angiotensinogen (AGT), cytochrome P450 family 11-subfamily ${\beta}$-2 ($CYP11{\beta}$-2), epithelial sodium channel (ENaC), G-protein b3 subunit (GNB3), G protein-coupled receptor kinases type 4 (GRK4 A142V, GRK4 A486V), $11{\beta}$-hydroxysteroid dehydrogenase type-2 (HSD $11{\beta}$-2), neural precursor cell-expressed developmentally down regulated 4 like (NEDD4L),and solute carrier family 12(sodium/chloride transporters)-member 3 (SLC 12A3). We found that polymorphisms of salt-sensitive genes such as ACE, $CYP11{\beta}$-2, GRK4, SLC12A3, and GNB3 may be positively associated with human obesity. Conclusion: Despite gender, ethnic, and age differences in genetics studies, hypertensive obese children and adults who are carriers of specific salt-sensitive genes are recommended to reduce their sodium intake. We believe that our findings can contribute to the prevention of early-onset of chronic diseases in obese children by facilitating personalized diet-management of obesity from childhood to adulthood.

• 고려인삼학회:학술대회논문집
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• 고려인삼학회 2003년도 추계 총회 및 학술대회
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• pp.30-31
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• 2003

• Biomolecules & Therapeutics
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• 제27권6호
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• pp.514-521
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• 2019

G protein-coupled receptors (GPCRs) are membrane receptors whose agonist-induced dynamic conformational changes trigger heterotrimeric G protein activation, followed by GRK-mediated phosphorylation and arrestin-mediated desensitization. Cytosolic regions of GPCRs have been studied extensively because they are direct contact sites with G proteins, GRKs, and arrestins. Among various cytosolic regions, the role of helix 8 is least understood, although a few studies have suggested that it is involved in G protein activation, receptor localization, and/or internalization. In the present study, we investigated the role of helix 8 in dopamine receptor signaling focusing on dopamine D1 receptor (D1R) and dopamine D2 receptor (D2R). D1R couples exclusively to Gs, whereas D2R couples exclusively to Gi. Bioinformatic analysis implied that the sequences of helix 8 may affect GPCR-G protein coupling selectivity; therefore, we evaluated if swapping helix 8 between D1R and D2R changed G protein selectivity. Our results suggest that helix 8 is not involved in D1R-Gs or D2R-Gi coupling selectivity. Instead, we observed that D1R with D2R helix 8 or D1R with an increased number of hydrophobic residues in helix 8 relative to wild-type showed diminished ${\beta}$-arrestin-mediated desensitization, resulting in increased Gs signaling.

• 한국농림기상학회지
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• 제23권4호
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• pp.235-250
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• 2021

본 연구에서는 '한국 김제의 전형적인 벼 경작 시스템이 기후스마트농업(CSA)의 삼중 도전에 어떻게 부합하고 있는가?'라는 질문에 답하기 위해, (1) 벼 경작 시스템의 에너지, 물, 탄소 및 정보의 흐름을 직접 관측하였고, (2) 생산성/효율성, 온실가스 방출/흡수 및 회복성을 평가할 수 있는 다양한 측정도구(metrics)를 사용하여 기후스마트농업의 관점에서 평가하였다. 국내 플럭스 관측망인 KoFlux 관측지의 하나인 김제의 대표적인 벼 경작 시스템에서 3년간(2011, 2012, 2014)의 생육기간 동안 에디공분산 기술을 사용하여 에너지, 물, 이산화탄소 및 메탄 플럭스의 흐름을 모니터링하였다. 생산 효율성 평가를 위해서는 총일차생산량(GPP), 생태계 호흡량(RE), 곡물 수확량, 빛사용효율(LUE), 물사용효율(WUE), 및 탄소흡수효율(CUE)을 지표로 사용하였다. 온실가스 정량화를 위해서는, 이산화탄소 플럭스(F_CO2)와 메탄 플럭스(F_CH4)의 경우 직접 관측한 자료를 사용하였고, 아산화질소 플럭스(F_N2O)는 IPCC지침에 따라 간접적으로 산출한 자료를 사용하였다. 회복성 평가를 위해서는 자기-조직화(self-organization, S) 지표를 사용하였으며, 벼 경작 시스템에서 가장 포괄적인 세 과정(총일차생산, 메탄플럭스, 증발산)을 대상으로 정보이론을 사용하여 정량화 하였다. 결과에 따르면, 3년 간의 생육 기간 중 2011년이 상대적으로 CSA 삼중 목표를 모두 성취하였으나, 이어지는 2012년과 2014년에 모두 생산량이 감소하고 온실가스 방출이 크게 증가하여 기후스마트 한 관리가 이루어지지 않은 것으로 보인다. 3년 생육기간을 평균한 CSA 지표의 값과 범위의 경우, 생산성에 관련된 지표들은 문헌에 보고된 다른 연구 결과와 비교할 때 대부분 중-상위의 범위에 속했으나, 온실가스 완화의 경우 평균 이하였고, 회복성은 높았지만 보고된 자료가 없어 비교하지 못했다. 기후스마트한 벼재배를 위해서는, 1) 이해 관계자들이 함께 목적에 맞게 목표의 우선순위를 정하고('거버넌스'), 2) CSA 지표를 분석한 결과로부터 얻어진 되먹임(feedback) ('모니터링') 정보를 기반으로, 3) 상황에 맞는 적절한 개입('관리'), 즉 거버넌스/관리/모니터링의 삼합으로 이루어지는 비저니어링이 필요함을 시사한다.