Maitotoxin activates a nonselective cation channel and a P2Z/P2X7-like cytolytic pore in human skin fibroblasts
Maitotoxin activates a nonselective cation channel and a P2Z/P2X7-like cytolytic pore in human skin fibroblasts
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DOI：
10.1152/ajpcell.1999.277.4.c755
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发表时间：
1999-10-01
影响因子：
5.5
通讯作者：
Estacion, M
中科院分区：
文献类型：
--
作者：
Schilling, WP;Sinkins, WG;Estacion, M
麦芽毒素 (MTX) 是一种有效的细胞溶解剂，可激活几乎所有类型细胞中的 Ca2+ 进入和非选择性阳离子通道。所涉及的通道的身份和导致细胞裂解的生化事件仍然未知。在本研究中，检测了 MTX 对人皮肤成纤维细胞质膜通透性的影响。 MTX 产生时间和浓度依赖性的胞质游离 Ca2+ 浓度增加，该浓度依赖于细胞外 Ca2+，并且对细胞外镧系元素的阻断相对不敏感。 MTX 还使质膜对较大分子的渗透性产生时间和浓度依赖性的增加，如 1) 乙锭 (314 Da) 的摄取，2) YO-PRO-1 (375 Da) 的摄取，3) 细胞内 fura 2 (636 Da) 的释放，4) POPO-3 (715 Da) 的摄取，以及最终 5) 乳酸脱氢酶的释放（相对分子质量140,000）。在单细胞水平上，YO-PRO-1 的摄取与有机阳离子 N-甲基-D-葡萄糖胺 (167 Da) 携带的大 MTX 诱导膜电流的出现及时相关。因此，MTX 最初激活 Ca2+ 渗透性阳离子通道，随后诱导大孔的形成。 MTX 对质膜通透性的这些影响与多种细胞类型中 P2Z/P2X(7) 受体激活的影响相似，这提出了 MTX 和 P2Z/P2X7 受体刺激激活共同溶细胞孔的有趣可能性。
Maitotoxin (MTX), a potent cytolytic agent, activates Ca2+ entry sia nonselective cation channels in virtually all types of cells. The identity of the channels involved and the biochemical events leading to cell lysis remain unknown. In the present study, the effect of MTX on plasmalemmal permeability of human skin fibroblasts was examined. MTX produced a time- and concentration-dependent increase in cytosolic free Ca2+ concentration that depended on extracellular Ca2+ and was relatively insensitive to blockade by extracellular lanthanides. MTX also produced a time- and concentration-dependent increase in plasmalemma permeability to larger molecules as indicated by 1) uptake of ethidium (314 Da), 2) uptake of YO-PRO-1 (375 Da), 3) release of intracellular fura 2 (636 Da), 4) uptake of POPO-3 (715 Da), and, ultimately, 5) release of lactate dehydrogenase (relative molecular weight of 140,000). At the single cell level, uptake of YO-PRO-1 correlated in time with the appearance of large MTX-induced membrane currents carried by the organic cation, N-methyl-D-glucamine (167 Da). Thus MTX initially activates Ca2+-permeable cation channels and later induces the formation of large pores. These effects of MTX on plasmalemmal permeability are similar to those seen on activation of P2Z/P2X(7) receptors ina variety of cell types, raising the intriguing possibility that MTX and P2Z/P2X7 receptor stimulation activate a common cytolytic pore.