Stabilization of ion channel protein by regulation of proteasome and its application to the individualizing atrial fibrillation.

通过蛋白酶体调节稳定离子通道蛋白及其在个体化心房颤动中的应用。

基本信息

项目摘要

Background : Previously we reported that ion channels responsible for chronic atrial fibrillation have been degraded by ubiquitin-proteasome, which was modification by antiarrhythmic agents. In the current study, we elucidated its underlying mechanism and application to the individualizing therapy for atrial fibrillation.Methods and Results : Na^+ channel blockers, but not either Ca^<2+> antagonists or K^+ channel blockers, blocked 20S proteasome activity to stabilize the short-lived proteins including p53,IKK2 and Kv1.5 assessed by pulse-chase analysis, immnofluorescence and patch clamp techniques in transfected COS cells. To confirm that p53 stabilization by Na^+ channel blockers was secondary to proteasome inhibition, we examined whether Mdm2 (C438A) could block the drug effects. When co-expressed with Mdm2 (C438A), p53-FLAG was not at all ubiquitinated even when cells were treated with MG132 and this drug failed to increase the p53-FLAG protein level. Likewise, p53-FLAG was not ubiquitinated in cells treated with Na^+ channel blockers, which failed to increase the protein level. Na^+ channel blockers stabilized the short-lived Kir6.2 channel proteins like MG132. There were several SNPs on the lysine residues in the coding region of Kir6.2, suggesting SNPs can affect the extent of channel protein degradation.Conclusion : Expression of short-lived ion channels have been regulated by ubiquitin-proteasome, which can be modulated by Na^+ channel blockers. Based on the SNPs information, a pharmacological therapy to regulate proteasomal degradation of channel protein can be available for treating the patients with chronic atrial fibrillation.
背景:以前我们报道过慢性心房颤动的离子通道被泛素蛋白酶体降解,而泛素蛋白酶体被抗心律失常药物修饰。在本研究中,我们阐明了其潜在的机制及其在房颤个体化治疗中的应用。方法和结果:在转染的COS细胞中,Na^+通道阻滞剂,而不是Ca^<2+>拮抗剂或K^+通道阻滞剂,阻断20S蛋白酶体的活性,以稳定包括p53,IKK2和Kv1.5在内的短寿命蛋白,通过脉冲追踪分析,免疫荧光和膜片钳技术评估。为了证实Na^+通道阻滞剂对p53的稳定作用继发于蛋白酶体抑制,我们检测了Mdm2 (C438A)是否可以阻断药物作用。当p53-FLAG与Mdm2 (C438A)共表达时,即使用MG132处理细胞,p53-FLAG也完全没有泛素化,MG132也不能提高p53-FLAG的蛋白水平。同样,p53-FLAG在Na^+通道阻滞剂处理的细胞中没有泛素化,也没有增加蛋白水平。Na^+通道阻滞剂稳定了短寿命的Kir6.2通道蛋白,如MG132。Kir6.2编码区赖氨酸残基上存在多个snp,提示snp可以影响通道蛋白降解的程度。结论:短寿命离子通道的表达受泛素蛋白酶体的调控,而Na^+通道阻滞剂可调节短寿命离子通道的表达。基于snp信息,调节通道蛋白蛋白酶体降解的药物治疗可用于治疗慢性心房颤动患者。

项目成果

期刊论文数量(36)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
心筋型ATP感受性Kチャンネルはユビキチン/プロテアソーム系により機能性チャンネル蛋白が規定される。
心脏 ATP 敏感 K 通道的功能通道蛋白由泛素/蛋白酶体系统定义。
  • DOI:
  • 发表时间:
    2004
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Kurata Y;et al.;田中宏明
  • 通讯作者:
    田中宏明
Roles of L-type Ca2+ and delayed-rectifier K+ currents in sinoatrial node pacemaking:: insights from stability and bifurcation analyses of a mathematical model
State-dependent blocking actions of azimilide dihydrochlo-ride (NE-10064) on human cardiac Na(+) channels.
阿齐利特二盐酸盐 (NE-10064) 对人心脏 Na(+) 通道的状态依赖性阻断作用。
  • DOI:
  • 发表时间:
    2004
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Miake J;et al.
  • 通讯作者:
    et al.
Okamura T, et al.: "Abnormally High Expression of Proteasome Activator-gamma in Thyroid Neoplasm"The Journal of Clinical Endocrinology and Metabolism. 88(3). 1374-1383 (2003)
Okamura T 等人:“甲状腺肿瘤中蛋白酶体激活剂-γ 的异常高表达”《临床内分泌与代谢杂志》。
  • DOI:
  • 发表时间:
  • 期刊:
  • 影响因子:
    0
  • 作者:
  • 通讯作者:
Detection of the novel autoantibody (anti-UACA antibody) in patients with Graves' disease.
  • DOI:
    10.1016/j.bbrc.2004.06.162
  • 发表时间:
    2004-08
  • 期刊:
  • 影响因子:
    3.1
  • 作者:
    T. Ohkura;Shin‐ichi Taniguchi;Kazuhiro Yamada;N. Nishio;T. Okamura;Akio Yoshida;Keiichi Kamijou;S. Fukata;K. Kuma;Y. Inoue;I. Hisatome;S. Senju;Y. Nishimura;C. Shigemasa
  • 通讯作者:
    T. Ohkura;Shin‐ichi Taniguchi;Kazuhiro Yamada;N. Nishio;T. Okamura;Akio Yoshida;Keiichi Kamijou;S. Fukata;K. Kuma;Y. Inoue;I. Hisatome;S. Senju;Y. Nishimura;C. Shigemasa
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HISATOME Ichiro其他文献

NPC1L1依存性コレステロール輸送におけるORP10の役割
ORP10 在 NPC1L1 依赖性胆固醇转运中的作用
  • DOI:
  • 发表时间:
    2015
  • 期刊:
  • 影响因子:
    0
  • 作者:
    IKEDA Nobuhito;NAKAZAWA Natsumi;KURATA Yasutaka;YAURA Hisako;TAUFIQ Fikri;MINATO Hiroyuki;YOSHIDA Akio;NINOMIYA Haruaki;NAKAYAMA Yuji;KUWABARA Masanari;SHIRAYOSHI Yasuaki;HISATOME Ichiro;Ohnishi Y. et al.;仲宗根 眞恵 他
  • 通讯作者:
    仲宗根 眞恵 他
微小核の生成と微小核細胞の運命
微核的产生和微核细胞的命运
  • DOI:
  • 发表时间:
    2017
  • 期刊:
  • 影响因子:
    0
  • 作者:
    IKEDA Nobuhito;NAKAZAWA Natsumi;KURATA Yasutaka;YAURA Hisako;TAUFIQ Fikri;MINATO Hiroyuki;YOSHIDA Akio;NINOMIYA Haruaki;NAKAYAMA Yuji;KUWABARA Masanari;SHIRAYOSHI Yasuaki;HISATOME Ichiro;中山祐二,井上敏昭
  • 通讯作者:
    中山祐二,井上敏昭
ORP11 as an effector of Rab9
ORP11 作为 Rab9 的效应子
  • DOI:
  • 发表时间:
    2017
  • 期刊:
  • 影响因子:
    0
  • 作者:
    IKEDA Nobuhito;NAKAZAWA Natsumi;KURATA Yasutaka;YAURA Hisako;TAUFIQ Fikri;MINATO Hiroyuki;YOSHIDA Akio;NINOMIYA Haruaki;NAKAYAMA Yuji;KUWABARA Masanari;SHIRAYOSHI Yasuaki;HISATOME Ichiro;Ohnishi Y. et al.
  • 通讯作者:
    Ohnishi Y. et al.

HISATOME Ichiro的其他文献

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{{ truncateString('HISATOME Ichiro', 18)}}的其他基金

Deep learning-based identification of sinoatrial node-like pacemaker cells from SHOX2/HCN4 double positive cells differentiated from human iPS cells
基于深度学习从人iPS细胞分化的SHOX2/HCN4双阳性细胞中鉴定窦房结样起搏细胞
  • 批准号:
    20K08423
  • 财政年份:
    2020
  • 资助金额:
    $ 2.24万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Stabilization of KvLQT1 by Hsp70 in differentiiated cardiomyocytes derived from LQT1 iPS cells
Hsp70 在源自 LQT1 iPS 细胞的分化心肌细胞中稳定 KvLQT1
  • 批准号:
    25670110
  • 财政年份:
    2013
  • 资助金额:
    $ 2.24万
  • 项目类别:
    Grant-in-Aid for Challenging Exploratory Research
Establishment of human pluripotent stem cell-derived pace-making cells using physiological approach and its application to the regenerative medicine
生理学方法建立人多能干细胞来源的起搏细胞及其在再生医学中的应用
  • 批准号:
    23659112
  • 财政年份:
    2011
  • 资助金额:
    $ 2.24万
  • 项目类别:
    Grant-in-Aid for Challenging Exploratory Research
Establishment of ES cell-derived biological pacemaker using ion channel and its application to bradycardia arrhythmias
ES细胞源离子通道生物起搏器的建立及其在心动过缓心律失常中的应用
  • 批准号:
    20590866
  • 财政年份:
    2008
  • 资助金额:
    $ 2.24万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Mechanism on Hsp70-induced stabilization of ion channel and its application to the treatment for atrial fibrillation
Hsp70诱导离子通道稳定的机制及其在房颤治疗中的应用
  • 批准号:
    18590775
  • 财政年份:
    2006
  • 资助金额:
    $ 2.24万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Mechanisms on the degradation of ion channel proteins and their modification by antiarrythmic agents
离子通道蛋白的降解机制及其抗心律失常药物的修饰
  • 批准号:
    13670713
  • 财政年份:
    2001
  • 资助金额:
    $ 2.24万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Novel mechanism on the ischemic preconditioning : Role of AMP deaminase family for adenosine production
缺血预处理的新机制:AMP 脱氨酶家族在腺苷生产中的作用
  • 批准号:
    11670680
  • 财政年份:
    1999
  • 资助金额:
    $ 2.24万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Mechanisms on the reperfusion arrythmias and the protection from reperfusion arrythmias : Redox reguration of the cardiac ion channels
再灌注心律失常的机制和再灌注心律失常的保护:心脏离子通道的氧化还原调节
  • 批准号:
    09670720
  • 财政年份:
    1997
  • 资助金额:
    $ 2.24万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)

相似海外基金

Collaborative Research: FET: Small: Reservoir Computing with Ion-Channel-Based Memristors
合作研究:FET:小型:基于离子通道忆阻器的储层计算
  • 批准号:
    2403559
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    2024
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    $ 2.24万
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    Standard Grant
Collaborative Research: FET: Small: Reservoir Computing with Ion-Channel-Based Memristors
合作研究:FET:小型:基于离子通道忆阻器的储层计算
  • 批准号:
    2403560
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    2024
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The role of cell surface mechanics in activating the mechanosensitive ion channel Piezo1
细胞表面力学在激活机械敏感离子通道 Piezo1 中的作用
  • 批准号:
    BB/X015831/1
  • 财政年份:
    2023
  • 资助金额:
    $ 2.24万
  • 项目类别:
    Research Grant
Distinct Ion Channel Pools and Intercalated Disk Nanoscale Structure Regulate Cardiac Conduction
独特的离子通道池和闰盘纳米级结构调节心脏传导
  • 批准号:
    10676368
  • 财政年份:
    2023
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    $ 2.24万
  • 项目类别:
Sensory Ion Channel Modulation by Bioactive Lipids
生物活性脂质对感觉离子通道的调节
  • 批准号:
    10622095
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    $ 2.24万
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Understanding polymodal gating of a lysosomal ion channel
了解溶酶体离子通道的多模式门控
  • 批准号:
    BB/W01551X/1
  • 财政年份:
    2023
  • 资助金额:
    $ 2.24万
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    Research Grant
Functional analysis of ion channel-type orphan receptor expressed in the myenteric plexus.
肌间丛表达的离子通道型孤儿受体的功能分析。
  • 批准号:
    23K06308
  • 财政年份:
    2023
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    $ 2.24万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Intracellular functions and mechanisms of alphavirus ion channel 6K
甲病毒离子通道6K的细胞内功能和机制
  • 批准号:
    10727819
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    $ 2.24万
  • 项目类别:
Sensory Ion Channel Modulation by Bioactive Lipids
生物活性脂质对感觉离子通道的调节
  • 批准号:
    10978347
  • 财政年份:
    2023
  • 资助金额:
    $ 2.24万
  • 项目类别:
Development of novel optogenetics tools employing gigantic ion-channel complex
利用巨大离子通道复合体开发新型光遗传学工具
  • 批准号:
    23K18090
  • 财政年份:
    2023
  • 资助金额:
    $ 2.24万
  • 项目类别:
    Grant-in-Aid for Challenging Research (Exploratory)
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