Increased free intracellular Ca2+ by toxic agents: an index of potential neurotoxicity?
Increased free intracellular Ca2+ by toxic agents: an index of potential neurotoxicity?
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有毒物质增加细胞内游离 Ca2：潜在神经毒性的指标？
DOI：
10.1016/0165-6147(88)90025-9
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发表时间：
1988
影响因子：
13.8
通讯作者：
Bondy,SC
中科院分区：
文献类型：
--
作者：
Komulainen,H;Bondy,SC
在激素或神经递质信号传导过程中，Ca 2+既可以通过质膜的电压依赖性流入作为信使，也可以作为神经组织中的第二信使（即通过特定介质从细胞内储存释放）。从几个实验的结果表明，细胞钙代谢可能是一个目标的神经毒剂的行动。使用呋喃的乙酰氧基甲酯（一种荧光钙离子指示剂），最近的研究表明，几种已知的神经毒剂（甲基汞、三乙基铅、三乙基锡、三甲基锡、十氯酮）可导致突触体细胞内游离钙离子浓度的长期升高（[Ca 2 '] J in vitro 3 #4.在相同浓度范围内毒性较小或无神经毒性的类似物（二甲基锡、甲基锡、灭蚁灵）不影响Ca 2+水平的意义上，影响是特定的。神经毒性效价和[Ca 2 +] i之间的这种良好相关性提出了一个问题，即[Ca 2 +] i增加和神经毒性是否可能存在因果关系。此外，可能增加[Ca 2 +]，在体外被用来预测神经毒性？毒素可能通过两种不同的机制干扰Ca 2+代谢：通过击中调节[Ca 2 +] i的机器中的关键位点或通过过度刺激神经细胞，从而导致Ca 2+进入速率的增加。前一种类型的作用不太可能是特异性受体介导的;大多数干扰[Ca 2 +] i的化学物质可能作用于细胞Ca 2+调节过程。在ktter的情况下，可能涉及与离子通道相关的特定受体。刺激兴奋性氨基酸受体（特别是NMDA受体）的药物可能抑制这种神经毒性。N-甲基-D-天冬氨酸（NMDA）（在培养的脊髓神经元4中）和红藻氨酸和谷氨酸（在小脑颗粒细胞培养物中）已被证明增加[Ca 2 +] i。细胞内额外的游离Ca 2+可预期在刺激细胞内Ca 2+依赖性反应中具有活性，例如神经递质的自发释放12、蛋白质的磷酸化13和蛋白酶的活性14。另一方面，[Ca 2 +] Q的慢性升高激活了补偿7
In hormone or neurotransmitter signalling processes, Ca2+ may act both as a messenger by means of voltage-dependent influx through the plasma membrane, and as a second messenger (ie released from intracellular stores by specific mediators) in neural tissue’* 2. Results from several experiments suggest that cellular Ca2 metabolism may be a target for the action of neurotoxic agents. Using the acetoxymethyl ester of fura-(a fluorescent Ca2+ indicator), it has recently been shown that several known neurotoxic agents (methyl mercury, triethyl lead, triethyl tin, trimethyl tin, chlordecone) cause a prolonged elevation in synaptosomal concentration of intracellular free Cazt ([Ca2’] J in vitro3# 4. Effects were specific in the sense that less toxic or non-neurotoxic analogs (dimethyl tin, methyl tin, mirex) at the same concentration range did not affect the Ca2+ level. Such a good correlation between neurotoxic potency and [Ca2+] i raises the question whether increased [Ca2+], and neurotoxicity might be causally related. Moreover, might increased [Ca2+], in vitro be used to predict neurotoxicity? Toxins may interfere with Ca2+ metabolism by two different mechanisms: by hitting critical sites in the machinery that regulates [Ca*‘] i or by stimulating nerve cells excessively, thereby causin an increase in the rate of Ca2 Q entry. The former type of effect is unlikely to be specifically receptor mediated; most chemicals that interfere with [Ca2+] i probably act on cellular Ca2+-regulating processes. In the ktter case, specific receptors associated with ion channels are likely be involved. Agents stimulating receptors of excitatory amino acids (partlcularly NMDA receptors5) might exemplify this type of neurotoxicipiO. N-methyl-D-aspartic acid (NMDA (in cultured spinal cord neurons 4) and kainic acid and glutamate (in cerebellar granule cell culture”) have been shown to increase [Ca2+]Elevation of i [‘Ca2+] i has several implications. Extra free Ca2+ within the cell can be expected to be active in stimulation of intracellular Ca2+-dependent rekitions, such as spontaneous release of neurotransmitters12, phosphorylation of proteins13 and activity of proteases14. On the other hand, a chronic elevation of [Ca2Q activates compensate 7