Tang Xiang Dong, Garcia Maria L, Heinemann Stefan H, Hoshi Toshinori
Department of Physiology, University of Pennsylvania, 3700 Hamilton Walk, Philadelphia, Pennsylvania 19104, USA.
Nat Struct Mol Biol. 2004 Feb;11(2):171-8. doi: 10.1038/nsmb725. Epub 2004 Jan 25.
Vascular dysfunction is a hallmark of many diseases, including coronary heart disease, stroke and diabetes. The underlying mechanisms of these disorders, which are intimately associated with inflammation and oxidative stress caused by excess reactive oxygen species (ROS), have remained elusive. Here we report that ROS are powerful inhibitors of vascular smooth muscle calcium-dependent Slo1 BK or Maxi-K potassium channels, an important physiological determinant of vascular tone. By targeting a cysteine residue near the Ca(2+) bowl of the BK alpha subunit, H(2)O(2) virtually eliminates physiological activation of the channel, with an inhibitory potency comparable to a knockout of the auxiliary subunit BK beta 1. These results reveal a molecular structural basis for the vascular dysfunction involving oxidative stress and provide a solid rationale for a potential use of BK openers in the prevention and treatment of cardiovascular disorders.
血管功能障碍是包括冠心病、中风和糖尿病在内的许多疾病的一个标志。这些疾病的潜在机制与过量活性氧（ROS）引起的炎症和氧化应激密切相关，仍然难以捉摸。在这里，我们报告ROS是血管平滑肌钙依赖性Slo1 BK或大电导钙激活钾通道（Maxi-K钾通道）的强大抑制剂，而该通道是血管张力的一个重要生理决定因素。通过靶向BKα亚基Ca(2+)碗附近的一个半胱氨酸残基，H(2)O(2)几乎消除了该通道的生理激活，其抑制效力与辅助亚基BKβ1敲除相当。这些结果揭示了涉及氧化应激的血管功能障碍的分子结构基础，并为BK开放剂在预防和治疗心血管疾病中的潜在应用提供了坚实的理论依据。
