Departamento de Toxicología, Centro de Investigación Y de Estudios Avanzados del IPN, Apartado Postal 14-740, 07360, Ciudad de Mexico, Mexico.
Instituto de Investigaciones Oceanológicas, Universidad Autónoma de Baja California, 22860, Ensenada, Baja California, Mexico.
Neurochem Res. 2020 Jun;45(6):1365-1374. doi: 10.1007/s11064-019-02848-8. Epub 2019 Jul 30.
Glutamate is the major excitatory amino acid neurotransmitter in the vertebrate brain. It exerts its actions through the activation of specific plasma membrane receptors expressed in neurons and glial cells. Overactivation of glutamate receptors results in neuronal death, known as excitotoxicity. A family of sodium-dependent glutamate transporters enriched in glial cells are responsible of the vast majority of the removal of this amino acid form the synaptic cleft. Therefore, a precise and exquisite regulation of these proteins is required not only for a proper glutamatergic transmission but also for the prevention of an excitotoxic insult. Manganese is a trace element essential as a cofactor for several enzymatic systems, although in high concentrations is involved in the disruption of brain glutamate homeostasis. The molecular mechanisms associated to manganese neurotoxicity have been focused on mitochondrial function, although energy depletion severely compromises the glutamate uptake process. In this context, in this contribution we analyze the effect of manganese exposure in glial glutamate transporters function. To this end, we used the well-established model of chick cerebellar Bergmann glia cultures. A time and dose dependent modulation of [H]-D-aspartate uptake was found. An increase in the transporter catalytic efficiency, most probably linked to a discrete increase in the affinity of the transporter was detected upon manganese exposure. Interestingly, glucose uptake was reduced by this metal. These results favor the notion of a direct effect of manganese on glial cells, this in turn alters their coupling with neurons and might lead to changes in glutamatergic transmission.
谷氨酸是脊椎动物大脑中主要的兴奋性氨基酸神经递质。它通过激活神经元和神经胶质细胞中表达的特定质膜受体发挥作用。谷氨酸受体的过度激活会导致神经元死亡，称为兴奋性毒性。富含神经胶质细胞的一组钠依赖性谷氨酸转运体负责将这种氨基酸从突触间隙中大量去除。因此，这些蛋白质的精确和精细调节不仅对于适当的谷氨酸能传递是必需的，而且对于防止兴奋性损伤也是必需的。锰是一种必需的微量元素，作为几种酶系统的辅助因子，尽管在高浓度下，它参与了大脑谷氨酸稳态的破坏。与锰神经毒性相关的分子机制集中在线粒体功能上，尽管能量耗竭严重损害了谷氨酸摄取过程。在这种情况下，在本研究中，我们分析了锰暴露对神经胶质谷氨酸转运体功能的影响。为此，我们使用了成熟的鸡小脑伯格曼神经胶质细胞培养模型。发现[H]-D-天冬氨酸摄取随时间和剂量而变化。在锰暴露后，检测到转运体催化效率的增加，这很可能与转运体亲和力的离散增加有关。有趣的是，这种金属会减少葡萄糖的摄取。这些结果支持了锰对神经胶质细胞直接作用的观点，这反过来又改变了它们与神经元的偶联，并可能导致谷氨酸能传递的变化。
