Denny M F, Atchison W D
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, USA.
Neurotoxicology. 1996 Spring;17(1):47-61.
Mercurials such as Hg2+ and methylmercury (MeHg) are environmental contaminants. Both are neurotoxic upon chronic and acute exposure, however, these toxic manifestations are distinct. The mechanisms underlying this cytotoxicity remain unknown, but may be related to a disruption in divalent cation homeostasis because both disrupt Ca(2+)-dependent processes in several model systems. These effects include a block in nerve-evoked neurotransmitter release as well as an increase in spontaneous transmitter release. This suggests that mercurials simultaneously decrease Ca2+ influx following nerve stimulation, and increase intracellular Ca2+ concentration ([Ca2+]i) in the nerve terminal. Although these effects appear to be at odds, they can be justified mechanistically. Both Hg2+ and MeHg block voltage-activated Ca2+ channels in the nerve terminal. The mechanism of block by these mercurials is different, since Hg2+ and MeHg are competitive and noncompetitive inhibitors of Ca2+ influx, respectively. The functional consequence in both instances remains decreased Ca2+ influx into the nerve terminal following the invasion of an action potential leading to decreased nerve-evoked release of neurotransmitter. The effects of mercurials on voltage-activated Ca2+ channels are distinct from those which mediate the increases in spontaneous transmitter release. Reducing extracellular Ca2+ concentration ([Ca2+]e) decreased, but did not prevent, the mercurial-induced increases in spontaneous transmitter release, suggesting that both intra- and extracellular sources of Ca2+ contribute to mercurial-induced elevations in [Ca2+]i in a nerve terminals. The effects of MeHg on divalent cation homeostasis have been studied using isolated nerve terminals from the rat brain (synaptosomes) and cells in culture (NG108-15 and isolated cerebellar granule cells) loaded with the Ca(2+)-selective fluorescent indicator fura-2. In synaptosomes, MeHg caused an Ca(2+)e-independent elevation in intrasynaptosomal Zn2+ concentration ([Zn2+]i) as well as an Ca(2+)e-dependent elevation in [Ca2+]i. The elevations in [Zn2+]i and [Ca2+]i were mediated by release of Zn2+ from soluble synaptosomal proteins and increased plasma membrane permeability, respectively. In NG108-15 cells, the effects of MeHg on divalent cation concentrations were more complex. First, MeHg mobilized Ca2+ from an intracellular store sensitive to inositol-1,4,5-tris-phosphate (IP3) which was independent of IP3 generation. Second, MeHg increased the intracellular concentration of an endogenous polyvalent cation, possibly Zn2+. Finally, MeHg caused an increase in the plasma membrane permeability to Ca2+ which was attenuated by high concentrations of the voltage-activated Ca2+ channel blocker nifedipine or by the voltage-activated Na+ channel blocker tetrodotoxin (TTX). While these studies demonstrate mercurials interfere with divalent cation regulation in neuronal systems, the consequences of these effects are not yet known.
汞化合物，如Hg2+和甲基汞（MeHg），是环境污染物。二者在长期和急性暴露时均具有神经毒性，然而，这些毒性表现有所不同。这种细胞毒性的潜在机制尚不清楚，但可能与二价阳离子稳态的破坏有关，因为二者在多个模型系统中均会干扰依赖Ca(2+)的过程。这些影响包括神经诱发的神经递质释放受阻以及自发递质释放增加。这表明汞化合物在神经刺激后同时减少Ca2+内流，并增加神经末梢内的细胞内Ca2+浓度（[Ca2+]i）。尽管这些影响似乎相互矛盾，但从机制上可以得到解释。Hg2+和MeHg均会阻断神经末梢中的电压激活Ca2+通道。这些汞化合物的阻断机制不同，因为Hg2+和MeHg分别是Ca2+内流的竞争性和非竞争性抑制剂。在这两种情况下，其功能后果都是在动作电位侵入后，Ca2+流入神经末梢减少，导致神经诱发的神经递质释放减少。汞化合物对电压激活Ca2+通道的影响与介导自发递质释放增加的影响不同。降低细胞外Ca2+浓度（[Ca2+]e）可减少但不能阻止汞化合物诱导的自发递质释放增加，这表明细胞内和细胞外的Ca2+来源均有助于汞化合物诱导神经末梢内[Ca2+]i升高。使用负载Ca(2+)选择性荧光指示剂fura-2的大鼠脑分离神经末梢（突触体）和培养细胞（NG108-15和分离的小脑颗粒细胞）研究了MeHg对二价阳离子稳态的影响。在突触体中，MeHg导致突触体内Zn2+浓度（[Zn2+]i）出现不依赖Ca(2+)e的升高以及[Ca2+]i出现依赖Ca(2+)e的升高。[Zn2+]i和[Ca2+]i的升高分别由可溶性突触体蛋白释放Zn2+和质膜通透性增加介导。在NG108-15细胞中，MeHg对二价阳离子浓度的影响更为复杂。首先，MeHg从对肌醇-1,4,5-三磷酸（IP3）敏感的细胞内储存库中动员Ca2+，这与IP3的产生无关。其次，MeHg增加了一种内源性多价阳离子（可能是Zn2+）的细胞内浓度。最后，MeHg导致质膜对Ca2+的通透性增加，高浓度的电压激活Ca2+通道阻滞剂硝苯地平或电压激活Na+通道阻滞剂河豚毒素（TTX）可减弱这种通透性增加。虽然这些研究表明汞化合物会干扰神经元系统中的二价阳离子调节，但其这些影响的后果尚不清楚。
