Ikeda M, Komachi H, Sato I, Himi T, Yuasa T, Murota S
Department of Physiological Chemistry, Graduate School, Tokyo Medical and Dental University, Japan.
J Neurosci Res. 1999 Feb 1;55(3):352-6. doi: 10.1002/(SICI)1097-4547(19990201)55:3<352::AID-JNR10>3.0.CO;2-3.
A free radical, nitric oxide (NO), besides being a messenger molecule in the brain, becomes a neurotoxin if overproduced. We recently reported that methylmercury (MeHg) induces neuronal NO synthase (nNOS) in Purkinje cells. In the present study, we examined the distribution and the mechanism of nNOS induction by MeHg. Subcutaneous administration of MeHg chloride to mice, 10 mg/kg/day for 9 days, increased calcium-dependent NOS activity to 60% more than the controls only in the cerebellum but not in other brain regions. The Western blots showed a comparable increase in nNOS protein in the cerebellum. A N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801, did not block, but rather enhanced, the increase in the nNOS activity. Another NMDA antagonist, 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), did not affect the nNOS activity. The Western blots of protein kinase C (PKC), which is an important cofactor regulating nNOS, did not change after the administration of MeHg. These results show that MeHg induces biologically active nNOS selectively in the cerebellum. The induction is independent of PKC and is not reduced by the blockade of the NMDA receptor.
自由基一氧化氮（NO），除了作为大脑中的信使分子外，如果产生过量则会成为一种神经毒素。我们最近报道，甲基汞（MeHg）可诱导浦肯野细胞中的神经元型一氧化氮合酶（nNOS）。在本研究中，我们研究了MeHg诱导nNOS的分布及机制。给小鼠皮下注射氯化甲基汞，剂量为10mg/kg/天，持续9天，结果显示，仅在小脑而非其他脑区，钙依赖性一氧化氮合酶活性比对照组增加了60%。蛋白质免疫印迹法显示，小脑中nNOS蛋白也有相应增加。N-甲基-D-天冬氨酸（NMDA）受体拮抗剂MK-801并未阻断，反而增强了nNOS活性的增加。另一种NMDA拮抗剂3-(2-羧基哌嗪-4-基)-丙基-1-磷酸（CPP）对nNOS活性没有影响。作为调节nNOS的重要辅助因子，蛋白激酶C（PKC）的蛋白质免疫印迹结果在给予MeHg后没有变化。这些结果表明，MeHg在小脑中选择性地诱导具有生物活性的nNOS。这种诱导独立于PKC，并且不会因NMDA受体的阻断而降低。
