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首页> 外文期刊>American Journal of Physiology >Differential role of IK and BK potassium channels as mediators of intrinsic and extrinsic apoptotic cell death
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Differential role of IK and BK potassium channels as mediators of intrinsic and extrinsic apoptotic cell death

机译：IK和BK钾通道作为内在和外在凋亡细胞死亡介质的不同作用

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An important event during apopto-sis is regulated cell condensation known as apoptotic volume decrease (AVD). Ion channels have emerged as essential regulators of this process mediating the release of K~+ and Cl~-, which together with osmotically obliged water, results in the condensation of cell volume. Using a Grade IV human glioblastoma cell line, we examined the contribution of calcium-activated K~+ channels (K_(Ca) channels) to AVD after the addition of either staurosporine (Stsp) or TNF-alpha-related apoptosis-inducing ligand (TRAIL) to activate the intrinsic or extrinsic pathway of apoptosis, respectively. We show that AVD can be inhibited in both pathways by high extracellular K~+ or the removal of calcium. However, BAPTA-AM was only able to inhibit Stsp-initiated AVD, whereas TRAIL-induced AVD was unaffected. Specific K_(Ca) channel inhibitors revealed that Stsp-induced AVD was dependent on K~+ efflux through intermediate-conductance calcium-activated potassium (IK) channels, while TRAIL-induced AVD was mediated by large-conductance calcium-activated potassium (BK) channels. Fura-2 imaging demonstrated that Stsp induced a rapid and modest rise in calcium that was sustained over the course of AVD, while TRAIL produced no detectable rise in global intracellular calcium. Inhibition of IK channels with clotrimazole or l-[(2-chloro-phenyl) diphenylmethyl]-1H-pyrazole (TRAM-34) blocked downstream caspase-3 activation after Stsp addition, while paxilline, a specific BK channel inhibitor, had no effect. Treatment with ionomy-cin also induced an IK-dependent cell volume decrease. Together these results show that calcium is both necessary and sufficient to achieve volume decrease and that the two major pathways of apoptosis use unique calcium signaling to efflux K~+ through different K_(Ca) channels.
机译：凋亡过程中的一个重要事件是调节细胞凝集，称为凋亡体积减少（AVD）。离子通道已成为该过程的重要调节剂，介导K +和Cl〜-的释放，以及渗透性水分，导致细胞体积的凝聚。我们使用IV级人类胶质母细胞瘤细胞系，研究了在添加星形孢菌素（Stsp）或TNF-α相关的凋亡诱导配体后，钙激活的K〜+通道（K_（Ca）通道）对AVD的贡献（ TRAIL）分别激活细胞凋亡的内在或外在途径。我们表明，高细胞外钾离子或钙的去除可在两种途径中抑制AVD。但是，BAPTA-AM仅能抑制Stsp启动的AVD，而TRAIL诱导的AVD则不受影响。特定的K_（Ca）通道抑制剂显示，Stsp诱导的AVD通过中电导钙激活的钾（IK）通道依赖于K〜+流出，而TRAIL诱导的AVD由大电导钙激活的钾（BK）介导。 ）频道。 Fura-2成像表明，Stsp诱导了钙的快速而适度的升高，该升高在AVD的过程中得以维持，而TRAIL却未检测到总体细胞内钙的升高。添加Stsp后，用克霉唑或1-[（（2-氯-苯基）二苯甲基] -1H-吡唑（TRAM-34）抑制IK通道可阻断下游caspase-3的活化，而特异的BK通道抑制剂Paxilline则无作用。用离子霉素处理还诱导IK依赖性细胞体积减少。这些结果共同表明，钙是实现体积减少的必要条件和充分条件，并且凋亡的两个主要途径使用独特的钙信号传导通过不同的K_（Ca）通道流出K〜+。

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