Chlorpromazine-Induced Changes in Membrane Micro-Architecture Inhibit Thrombopoiesis in Rat Megakaryocytes
Chlorpromazine-Induced Changes in Membrane Micro-Architecture Inhibit Thrombopoiesis in Rat Megakaryocytes
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氯丙嗪诱导的膜微结构变化抑制大鼠巨核细胞的血小板生成
DOI：
10.1016/j.bbamem.2015.08.013
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Tachi M
中科院分区：
文献类型：
--
作者：
Kazama I;Endo Y;Toyama H;Ejima Y;Matsubara M;Baba A;Tachi M
氯丙嗪常引起严重和持续的血小板减少症。一些临床研究表明，在这种药物诱导的血小板减少症中存在一种未知的机制，可能直接影响巨核细胞的血小板生成。正如我们先前在大鼠腹腔肥大细胞或脂肪细胞中所证明的，氯丙嗪是两亲性的，并且优先分配到质膜的脂质双层中。因此，它可以诱导巨核细胞膜表面的一些结构变化，从而影响血小板生成的过程。在本研究中，采用标准的膜片钳全细胞记录技术，我们研究了氯丙嗪对大鼠巨核细胞膜电容和Kv1.3通道电流的影响。通过细胞表面的电子显微镜成像，我们还研究了氯丙嗪对巨核细胞膜微结构的影响。氯丙嗪显著降低巨核细胞的膜电容，表明内陷质膜的数量减少，这是没有检测到的荧光成像技术。如电子显微镜所示，氯丙嗪实际上改变了巨核细胞的膜微结构，并可能阻止细胞中前血小板形成的过程。该药物持续降低巨核细胞的膜电容，几乎完全和不可逆地抑制Kv1.3通道电流。这项研究首次证明，氯丙嗪可能会抑制血小板生成的过程中持续巨核细胞，检测的膜电容的长期持续下降和不可逆的抑制Kv1.3通道电流。氯丙嗪引起的膜微结构的变化被认为是其持续作用的原因。
Chlorpromazine often causes severe and persistent thrombocytopenia. Several clinical studies have suggested the presence of an as-yet-unknown mechanism in this drug-induced thrombocytopenia, by which the platelet production from megakaryocytes may directly be affected. As we previously demonstrated in rat peritoneal mast cells or adipocytes, chlorpromazine is amphiphilic and preferentially partitioned into the lipid bilayers of the plasma membrane. Therefore, it can induce some structural changes in the megakaryocyte membrane surface and thus affect the process of thrombopoiesis. In the present study, employing the standard patch-clamp whole-cell recording technique, we examined the effects of chlorpromazine on the membrane capacitance and Kv1.3-channel currents in rat megakaryocytes. By electron microscopic imaging of the cellular surface, we also examined the effects of chlorpromazine on the membrane micro-architecture of megakaryocytes. Chlorpromazine markedly decreased the membrane capacitance of megakaryocytes, indicating the decreased number of invaginated plasma membranes, which was not detected by the fluorescent imaging techniques. As shown by electron microscopy, chlorpromazine actually changed the membrane micro-architecture of megakaryocytes, and was likely to halt the process of pro-platelet formation in the cells. This drug persistently decreased the membrane capacitance and almost totally and irreversibly inhibited the Kv1.3-channel currents in megakaryocytes. This study demonstrated for the first time that chlorpromazine is likely to inhibit the process of thrombopoiesis persistently in megakaryocytes, as detected by the long-lasting decrease in the membrane capacitance and the irreversible suppression of the Kv1.3-channel currents. Chlorpromazine-induced changes in the membrane micro-architecture are thought to be responsible for its persistent effects.