A Role of BK Channel in Regulation of Ca2 Channel in Ventricular Myocytes by Substrate Stiffness
A Role of BK Channel in Regulation of Ca2 Channel in Ventricular Myocytes by Substrate Stiffness
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BK 通道在基质硬度调节心室肌细胞 Ca2 通道中的作用
DOI：
10.1016/j.bpj.2017.01.036
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发表时间：
2017
影响因子：
3.4
通讯作者：
Feng Xiqiao
中科院分区：
文献类型：
--
作者：
Zhao Hucheng;Yu Yang;Wu Xiaoan;Liu Sisi;Liu Bailin;Du Jing;Li Bo;Jiang Linhua;Feng Xiqiao
基质硬度对于多种细胞功能至关重要，但赋予细胞机械敏感性的机制仍然难以捉摸。通过定制基板硬度与10倍的差异，我们发现，L型电压门控性钙通道电流密度是更大的鸡心室肌细胞培养的硬基板上比软基板。BK通道的阻断增加了软基底上的Ca 2+电流密度，从而消除了Ca 2+通道的基底刚度调节。在刚性基质上培养的细胞中，BK通道（包括在肌细胞中形成牵张激活BK通道的含STREX的α亚基）的表达和肌细胞中BK通道功能（以及异源表达含STREX的α亚基和β1亚基的HEK293细胞）降低。此外，在共表达心脏CaV1.2通道和含STREX的BK通道的HEK293细胞中，在刚性基底上的细胞中的Ca2+电流密度更大，这在单独表达CaV1.2通道或与STREX缺失的BK通道共表达的细胞中未观察到。这些结果提供了强有力的证据表明，牵张激活的BK通道通过底物硬度在心脏电压门控Ca 2+通道的功能调节中起关键作用，揭示了心室肌细胞中一种新的机械感受机制。
Substrate stiffness is crucial for diverse cell functions, but the mechanisms conferring cells with mechanosensitivity are still elusive. By tailoring substrate stiffness with 10-fold difference, we showed that L-type voltage-gated Ca2+channel current density was greater in chick ventricular myocytes cultured on the stiff substrate than on the soft substrate. Blockage of the BK channel increased the Ca2+current density on the soft substrate and consequently eliminated substrate stiffness regulation of the Ca2+channel. The expression of the BK channel, including the STREX-containingα-subunit that forms stretch-activated BK channel in myocytes and the BK channel function in myocytes (and also in HEK293 cells heterologously expressing STREX-containingα- andβ1-subunits) was reduced in cells cultured on the stiff substrate. Furthermore, in HEK293 cells coexpressing the cardiac CaV1.2 channel and STREX-containing BK channel, the Ca2+current density was greater in cells on the stiff substrate, which was not observed in cells expressing the CaV1.2 channel alone or coexpressing with the STREX-deleted BK channel. These results provide strong evidence to show that the stretch-activated BK channel plays a key role in functional regulation of cardiac voltage-gated Ca2+channel by substrate stiffness, revealing, to our knowledge, a novel mechanosensing mechanism in ventricular myocytes.