Hypoxia inhibits the cardiac I (K1) current through SUMO targeting Kir2.1 activation by PIP(2).
Hypoxia inhibits the cardiac I (K1) current through SUMO targeting Kir2.1 activation by PIP(2).
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DOI：
10.1016/j.isci.2022.104969
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发表时间：
2022-09-16
期刊：
影响因子：
5.8
通讯作者：
Plant, Leigh D.
中科院分区：
文献类型：
--
作者：
Xu, Yu;Yang, Yuchen;Chandrashekar, Aishwarya;Gada, Kirin D.;Masotti, Meghan;Baggetta, Austin M.;Connolly, Jenna G.;Kawano, Takeharu;Plant, Leigh D.
心血管疾病仍然是全世界死亡的主要原因。大多数死亡都是突然的，继发于冠状动脉闭塞，导致细胞氧水平迅速下降。急性缺氧会导致心律失常，导致电信号紊乱、传导阻滞和心肌跳动不协调。尽管人们认识到急性缺氧会扰乱心肌的电生理学，但其作用的机制基础仍然难以捉摸，从而阻碍了针对性治疗干预措施的发展。在这里，我们发现急性缺氧会激活心肌细胞中氧化还原敏感的 SUMO 途径，导致内向整流 K+ 通道 Kir2.1 快速抑制。我们发现 SUMO 化降低了膜磷脂磷脂酰肌醇 4,5-二磷酸 (PIP2) 对 Kir2.1 通道的激活。这些数据为急性缺氧的促心律失常作用提供了机制基础，并为理解 PIP2 在介导心血管疾病缺氧后遗症和 SUMOylation 中的核心作用提供了框架。急性缺氧抑制心肌细胞中的内向整流 K+ 电流、IK1 Kir2.1 通道快速 SUMO 化导致 IK1 缺氧抑制 SUMO 化降低 PIP2 激活 Kir2.1 通道的效力和功效 外源性 PIP2 类似物对抗 IK1 和 Kir2.1 通道的缺氧抑制 生物科学；分子生物学；细胞生物学
Cardiovascular diseases remain the leading cause of death worldwide. Most deaths are sudden and occur secondary to the occlusion of coronary arteries resulting in a rapid decrease in cellular oxygen levels. Acute hypoxia is proarrhythmic, leading to disordered electrical signals, conduction block, and uncoordinated beating of the myocardium. Although acute hypoxia is recognized to perturb the electrophysiology of heart muscle, the mechanistic basis for the effect has remained elusive, hampering the development of targeted therapeutic interventions. Here, we show that acute hypoxia activates the redox-sensitive SUMO pathway in cardiomyocytes, causing rapid inhibition of the inward-rectifying K+ channel, Kir2.1. We find that SUMOylation decreases the activation of Kir2.1 channels by the membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2). These data provide a mechanistic basis for the proarrhythmic effects of acute hypoxia and offer a framework for understanding the central role of PIP2 in mediating the sequelae of hypoxia and SUMOylation in cardiovascular disease. Acute hypoxia inhibits the inward rectifying K+ current, IK1 in cardiomyocytes Hypoxic inhibition of IK1 results from rapid SUMOylation of Kir2.1 channels SUMOylation decreases the potency and efficacy of PIP2 to activate Kir2.1 channels An exogenous PIP2 analog opposes hypoxic inhibition of IK1 and Kir2.1 channels Biological sciences; Molecular biology; Cell biology
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影响因子：
64.8
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