• 생명과학회지
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• 제19권10호
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• pp.1484-1488
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• 2009

가족성 저칼륨성 주기성 마비란 상염색체 우성 유전 질환으로 저칼륨혈증을 동반한 간헐적인 가역적 이완성 근육 마비를 특징으로 한다. 세포내 저류된 칼륨으로 인해 저칼륨혈증이 지속되고 근세포 활성이상으로 인해 마비가 발생하는 것으로 알려져 있다. 이러한 증상발현의 분자생물학적 기전을 확인하기 위해 세포 내 칼륨이온을 세포 밖으로 이동시키는 지연성 정류형 채널 단백질의 일종인 KCNQ3와 KCNQ5를 대상으로, 정상인과 환자에서 채취한 골격근 세포를 생리적 세포외 정상 칼륨농도인 4 mM과 탈분극 유도를 위한 고칼륨농도인 50mM에 노출시켜 단백질의 양적 변화 유무를 확인하였다. 유전자 발현양상을 확인하기 위해 mRNA의 양적 변화를 확인한 결과 모든 조건에서 유의한 변화가 관찰되지 않아 정상 칼륨조건과 고칼륨조건이 두 유전자발현의 변화를 야기하지 않음을 확인하였다. 그러나 단백질 양을 관찰한 결과 환자의 골격근 세포가 50 mM의 칼륨농도에 노출되는 경우 KCNQ3 단백질은 세포질 내에서 증가하고 세포막 내에서 감소하였다. 이는 환자의 골격근 세포가 고농도의 세포외 칼륨에 의해 탈분극 되는 경우 재분극에 중요한 기능을 담당하는 KCNQ3 채널 단백질이 세포질 내로 이동하여 재분극 형성의 장애를 초래하고 이로 인해 근세포 활성이 일어나지 않게 되어 마비를 유발할 수 있음을 시사하는 결과로 본 질환의 새로운 발병 기전을 설명할 수 있는 근거로 생각된다.

• EDISON SW 활용 경진대회 논문집
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• 제6회(2017년)
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• pp.665-671
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• 2017

Iks 칼륨 전류에 관여하는 KCNQ1유전자의 S140G 돌연변이는 심방세동에 영향을 미치는 대표적인 돌연변이 유전자로, 심방세동과 S140G 돌연변이의 상관관계를 밝히기 위한 연구들이 많이 진행되어 왔다. 하지만 S140G 돌연변이 유전자가 심방 세동 환자의 심실 반응에 영향을 미칠 수 있다는 선행연구를 비롯하여 심방과 심실의 활동전위에 영향을 미칠 수 있는 가능성이 있음에도 불구하고, KCNQ1 S140G 돌연변이 유전자의 심실세동에 대한 영향과 그 메커니즘에 대한 연구는 부족하다. 따라서 본 연구는 KCNQ1 S140G 돌연변이 유전자가 심실세동에 미치는 영향에 대한 컴퓨터 시뮬레이션 연구를 통해 그 상관관계를 밝히고자 하였다. 이를 위해 1차원 세포 모델을 비롯하여 2차원 심실세동 반응과 3차원 전기 생리학 및 기계적 수축 시뮬레이션을 진행하였다. 3차원의 전기생리학 및 기계적 수축 시뮬레이션에서는 심실의 박출 활동을 확인하기 위한 정상 박동 시뮬레이션과 심실 세동 발생시의 심실의 변화를 확인하기 위한 세동 시뮬레이션을 각각 진행하였다. 그 결과 KCNQ1 S140G 돌연변이로 인해 심실의 Iks가 증가되었으며, 그로 인해 심실의 활동 전위기간(APD)과 불응기(ERP)가 단축되는 것을 확인할 수 있었다. 또한 활동전위 지속 곡선(APDr)과 불응기 지속 곡선(ERPr)이 완만하게 나타났으며, 심근세포의 전도파장이 감소하였다. 3차원 정상 박동 시뮬레이션의 결과 표준형에서 보다 KCNQ1 S140G 돌연변이형에서 심실이 소모하는 ATP의 양과 박출계수가 감소하였다. 3차원 세동 시뮬레이션 결과 표준형에서는 심실세동이 종결되었으나, S140G 돌연변이 형에서는 심실세동이 종결되지않고 유지되었으며, 심실세동이 빠르게 발생하였다. 결론적으로, KCNQ1 S140G 돌연변이로 인해 증가된 심실의 Iks는 심실의 박출 효율을 감소시키고 심실세동을 발생시키고 유지시키며, 부정맥 발생의 위험성을 높일 수 있다.

• Journal of Ginseng Research
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• 제37권3호
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• pp.324-331
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• 2013

Channels formed by the co-assembly of the KCNQ1 subunit and the mink (KCNE1) subunit underline the slowly activating delayed rectifier $K^+$ channels ($I_{Ks}$) in the heart. This $K^+$ channel is one of the main pharmacological targets for the development of drugs against cardiovascular disease. Panax ginseng has been shown to exhibit beneficial cardiovascular effects. In a previous study, we showed that ginsenoside Rg3 activates human KCNQ1 $K^+$ channel currents through interactions with the K318 and V319 residues. However, little is known about the effects of ginsenoside metabolites on KCNQ1 $K^+$ alone or the KCNQ1 + KCNE1 $K^+$ ($I_{Ks}$) channels. In the present study, we examined the effect of protopanaxatriol (PPT) and compound K (CK) on KCNQ1 $K^+$ and $I_{Ks}$ channel activity expressed in Xenopus oocytes. PPT more strongly inhibited the $I_{Ks}$ channel currents than the currents of KCNQ1 $K^+$ alone in concentration- and voltage-dependent manners. The $IC_{50}$ values on $I_{Ks}$ and KCNQ1 alone currents for PPT were $5.18{\pm}0.13$ and $10.04{\pm}0.17{\mu}M$, respectively. PPT caused a leftward shift in the activation curve of $I_{Ks}$ channel activity, but minimally affected KCNQ1 alone. CK exhibited slight inhibition on $I_{Ks}$ and KCNQ1 alone $K^+$ channel currents. These results indicate that ginsenoside metabolites show limited effects on $I_{Ks}$ channel activity, depending on the structure of the ginsenoside metabolites.

• 대한의용생체공학회:의공학회지
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• 제38권3호
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• pp.123-128
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• 2017

Background and aims: The KCNQ1 S140G mutation involved in $I_{ks}$ channel is a typical gene mutation affecting atrial fibrillation. However, despite the possibility that the S140G gene mutation may affect not only atrial but also ventricular action potential shape and ventricular responses, there is a lack of research on the relationship between this mutation and ventricular fibrillation. Therefore, in this study, we analyzed the correlation and the influence of the KCNQ1 S140G mutant gene on ventricular fibrillation through computer simulation studies. Method: This study simulated a 3-dimensional ventricular model of the wild type(WT) and the S140G mutant conditions. It was performed by dividing into normal sinus rhythm simulation and reentrant wave propagation simulation. For the sinus rhythm, a ventricular model with Purkinje fiber was used. For the reentrant propagation simulation, a ventricular model was used to confirm the occurrence of spiral wave using S1-S2 protocol. Results: The result showed that 41% shortening of action potential duration(APD) was observed due to augmented $I_{ks}$ current in S140G mutation group. The shortened APD contributed to reduce wavelength 39% in sinus rhythm simulation. The shortened wavelength in cardiac tissue allowed re-entrant circuits to form and increased the probability of sustaining ventricular fibrillation, while ventricular electrical propagation with normal wavelength(20.8 cm in wild type) are unlikely to initiate re-entry. Conclusion: In conclusion, KCNQ1 S140G mutation can reduce the threshold of the re-entrant wave substrate in ventricular cells, increasing the spatial vulnerability of tissue and the sensitivity of the fibrillation. That is, S140G mutation can induce ventricular fibrillation easily. It means that S140G mutant can increase the risk of arrhythmias such as cardiac arrest due to heart failure.

• Molecules and Cells
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• 제37권9호
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• pp.656-663
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• 2014

Gintonin, a novel, ginseng-derived G protein-coupled lysophosphatidic acid (LPA) receptor ligand, elicits $[Ca^{2+}]_i$ transients in neuronal and non-neuronal cells via pertussis toxin-sensitive and pertussis toxin-insensitive G proteins. The slowly activating delayed rectifier $K^+$ ($I_{Ks}$) channel is a cardiac $K^+$ channel composed of KCNQ1 and KCNE1 subunits. The C terminus of the KCNQ1 channel protein has two calmodulin-binding sites that are involved in regulating $I_{Ks}$ channels. In this study, we investigated the molecular mechanisms of gintonin-mediated activation of human $I_{Ks}$ channel activity by expressing human $I_{Ks}$ channels in Xenopus oocytes. We found that gintonin enhances $I_{Ks}$ channel currents in concentration- and voltage-dependent manners. The $EC_{50}$ for the $I_{Ks}$ channel was $0.05{\pm}0.01{\mu}g/ml$. Gintonin-mediated activation 1 of the $I_{Ks}$ channels was blocked by an LPA1/3 receptor antagonist, an active phospholipase C inhibitor, an $IP_3$ receptor antagonist, and the calcium chelator BAPTA. Gintonin-mediated activation of both the $I_{Ks}$ channel was also blocked by the calmodulin (CaM) blocker calmidazolium. Mutations in the KCNQ1 $[Ca^{2+}]_i$/CaM-binding IQ motif sites (S373P, W392R, or R539W)blocked the action of gintonin on $I_{Ks}$ channel. However, gintonin had no effect on hERG $K^+$ channel activity. These results show that gintonin-mediated enhancement of $I_{Ks}$ channel currents is achieved through binding of the $[Ca^{2+}]_i$/CaM complex to the C terminus of KCNQ1 subunit.

• 농업과학연구
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• 제45권4호
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• pp.707-713
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• 2018

This study was done to search for positional candidate genes associated with the back fat thickness trait using a Genome-Wide Association Study (GWAS) in purebred Yorkshires (N = 1755). Genotype and phenotype analyses were done for 1,642 samples. As a result of the associations with back fat thickness using the Gemma program (ver. 0.93), when the genome-wide suggestive threshold was determined using the Bonferroni method ($p=1.61{\times}10^{-5}$), the single nucleotide polymorphism (SNP) markers with suggestive significance were identified in 1 SNP marker on chromosome 2 (MARC0053928; $p=3.65{\times}10^{-6}$), 2 SNP markers on chromosome 14 (ALGA0083078; $p=7.85{\times}10^{-6}$, INRA0048453; $p=1.27{\times}10^{-5}$), and 1 SNP marker on chromosome 18 (ALGA0120564; $p=1.44{\times}10^{-5}$). We could select positional candidate genes (KCNQ1, DOCK1, LOC106506151, and LOC110257583), located close to the SNP markers. Among these, we identified a potassium voltage-gated channel subfamily Q member gene (KCNQ1) and the dedicator of cytokinesis 1 (DOCK1) gene associated with obesity and Type-2 diabetes. The SNPs and haplotypes of the KCNQ1 and DOCK1 genes can contribute to understanding the genetic structure of back fat thickness. Additionally, it may provide basic data regarding marker assisted selection for a meat quality trait in pigs.

• Asian-Australasian Journal of Animal Sciences
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• 제22권6호
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• pp.893-899
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• 2009

Few studies have reported the existence of imprinted genes in cattle compared to the human and mouse. Genomic imprinting is expressed in monoallelic form and it depends on a single parent-specific form of the allele. Comparative analysis of mammals other than the human is a valuable tool for explaining the genomic basis of imprinted genes. In this study, we investigated 34 common imprinted genes in the human and mouse as well as 35 known non-imprinted genes in the human. We found short interspersed nuclear elements (SINEs), long interspersed nuclear elements (LINEs), and long terminal repeats (LTRs) in imprinted (human and mouse) and control (cattle) genes. Pair-wise comparisons for the three species were conducted using SINEs, LINEs, and LTRs. We also calculated 95% confidence intervals of frequencies of repetitive sequences for the three species. As a result, most genes had a similar interval between species. We found 11 genes with conserved SINEs, LINEs, and LTRs in the human, mouse, and cattle. In conclusion, eleven genes (CALCR, Grb10, HTR2A, KCNK9, Kcnq1, MEST, OSBPL5, PPP1R9A, Sgce, SLC22A18, and UBE3A) were identified as candidate imprinted genes in cattle.

• 대한두경부종양학회지
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• 제24권2호
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• pp.155-161
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• 2008

Head and neck squamous cell carcinoma(HNSCC) still has poor outcome, and laryngeal cancer is the most frequent subtype of HNSCC. Therefore, there is a need to develop novel treatments to improve the outcome of patients with HNSCC. It is critical to gain further understanding on the molecular and chromosomal alteration of HNSCC to identify novel therapeutic targets but genetic etiology of squamous cell carcinoma of the larynx is so complex that target genes have not yet been clearly identified. Array based CGH(array-CGH) allows investigation of general changes in target oncogenes and tumor suppressor genes, which should, in turn, lead to a better understanding of the cancer process. In this study, We used genomic wide array-CGH in tissue specimens to map genomic alterations found in laryngeal squamous cell carcinomas. As results, gains of MAP2, EPHA3, EVI1, LOC389174, NAALADL2, USP47, CTDP1, MASP1, AHRR, and KCNQ5, with losses of SRRM1L, ANKRD19, FLJ39303, ZNF141, DSCAM, GPR27, PROK2, ARPP-21, and B3GAT1 were observed frequently in laryngeal squamous cell carcinoma tissue specimens. These data about the patterns of genomic alterations could be a basic step for understanding more detailed genetic events in the carcinogenesis and also provide information for diagnosis and treatment in laryngeal squamous cell carcinoma. The high resolution of array-CGH combined with human genome database would give a chance to find out possible target genes which were gained or lost clones.