Chloride channels are necessary for full platelet phosphatidylserine exposure and procoagulant activity.
Chloride channels are necessary for full platelet phosphatidylserine exposure and procoagulant activity.
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DOI：
10.1038/cddis.2013.495
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发表时间：
2013-12-19
影响因子：
9
通讯作者：
Poole, A. W.
中科院分区：
文献类型：
--
作者：
Harper, M. T.;Poole, A. W.
血小板通过在坏死样细胞死亡过程中暴露磷脂酰丝氨酸而增强血管损伤部位的凝血酶生成。Anoctamin 6（Ano 6）是Ca 2+依赖性磷脂酰丝氨酸暴露所必需的，在斯科特综合征（一种罕见的出血性疾病）患者中存在缺陷。Ano 6也可能形成Cl−通道，尽管Cl−通量在血小板促凝血活性中的作用尚未研究。我们发现，Cl−通道阻断剂或细胞外Cl−的清除抑制激动剂诱导的磷脂酰丝氨酸暴露。然而，这不是由于直接抑制钙离子依赖的混乱，因为钙离子载体诱导的磷脂酰丝氨酸暴露是正常的。这意味着Ano 6在Ca 2 +-依赖性PS暴露中的作用可能不同于Ano 6作为Cl-通道的任何假定功能。相反，Cl−通道阻断抑制激动剂诱导的Ca 2+内流。重要的是，Cl−通道阻滞剂也阻止激动剂诱导的膜超极化，导致去极化。我们认为，这种超极化需要Cl−通过Cl−通道进入，维持Ca 2+进入的驱动力，并触发完整的磷脂酰丝氨酸暴露。这证明了Cl−通道在控制血小板死亡和促凝血活性中的新作用。
Platelets enhance thrombin generation at sites of vascular injury by exposing phosphatidylserine during necrosis-like cell death. Anoctamin 6 (Ano6) is required for Ca2+-dependent phosphatidylserine exposure and is defective in patients with Scott syndrome, a rare bleeding disorder. Ano6 may also form Cl− channels, though the role of Cl− fluxes in platelet procoagulant activity has not been explored. We found that Cl− channel blockers or removal of extracellular Cl− inhibited agonist-induced phosphatidylserine exposure. However, this was not due to direct inhibition of Ca2+-dependent scrambling since Ca2+ ionophore-induced phosphatidylserine exposure was normal. This implies that the role of Ano6 in Ca2+−dependent PS exposure is likely to differ from any putative function of Ano6 as a Cl− channel. Instead, Cl− channel blockade inhibited agonist-induced Ca2+ entry. Importantly, Cl− channel blockers also prevented agonist-induced membrane hyperpolarization, resulting in depolarization. We propose that Cl− entry through Cl− channels is required for this hyperpolarization, maintaining the driving force for Ca2+ entry and triggering full phosphatidylserine exposure. This demonstrates a novel role for Cl− channels in controlling platelet death and procoagulant activity.
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影响因子：
20.3
作者：
Braun, Attila;Varga-Szabo, David;Nieswandt, Bernhard
通讯作者：
Nieswandt, Bernhard
影响因子：
20.3
作者：
Bergmeier, Wolfgang;Oh-hora, Masatsugu;Feske, Stefan
通讯作者：
Feske, Stefan
影响因子：
10.4
作者：
Jones, M. L.;Harper, M. T.;Poole, A. W.
通讯作者：
Poole, A. W.
影响因子：
7.3
作者：
Harper, Matthew T.;Londono, Juan E. Camacho;Poole, Alastair W.
通讯作者：
Poole, Alastair W.
影响因子：
4
作者：
Harper, Matthew T.;Poole, Alastair W.
通讯作者：
Poole, Alastair W.