Ebadi M, Iversen P L, Hao R, Cerutis D R, Rojas P, Happe H K, Murrin L C, Pfeiffer R F
Department of Pharmacology, University of Nebraska College of Medicine, Omaha 68198-6260, USA.
Neurochem Int. 1995 Jul;27(1):1-22. doi: 10.1016/0197-0186(94)00164-p.
Many, but not all, zinc-containing neurons in the brain are a subclass of the glutamatergic neurons, and they are found predominantly in the telencephalon. These neurons store zinc in their presynaptic terminals and release it by a calcium-dependent mechanism. These "vesicular" pools of zinc are viewed as endogenous modulators of ligand- and voltage-gated ion channels. Metallothioneins (MTs) are low molecular weight zinc-binding proteins consisting of 25-30% cysteine, with no aromatic amino acids or disulfide bonds. The areas of the brain containing high contents of zinc such as the retina, the pineal gland, and the hippocampus synthesize unique isoforms of MT on a continuous basis. The four MT isoforms are thought to provide the neurons and glial elements with mechanisms to distribute, donate, and sequester zinc at presynaptic terminals; or buffer the excess zinc at synaptic junctions. In this cause, glutathione disulfide may participate in releasing zinc from MT. A similar nucleotide and amino acid sequence has made it difficult to obtain cDNA probes and antibodies capable of distinguishing indisputably among MT isoforms. MT-I and MT-II isoforms are found in the brain and in the peripheral tissues; MT-III isoform, possessing an additional seven amino acids, is expressed mostly in the brain and to a very minute extent in the intestine and pancreas; whereas MT-IV isoform is found in tissues containing stratified squamous epithelial cells. Since MTs are expressed in neurons that sequester zinc in their synaptic vesicles, the regulation of the expression of MT isoforms is extremely important in terms of maintaining the steady-state level of zinc and controlling redox potentials. The concentration of zinc has been shown to be altered in an extensive number of disorders of the central nervous system, including alcoholism. Alzheimer-type dementia, amyotrophic lateral sclerosis, Down's syndrome, epilepsy, Friedreich's ataxia, Guillaine-Barré syndrome, hepatic encephalopathy, multiple sclerosis, Parkinson's disease, Pick's disease, retinitis pigmentosa, retinal dystrophy, schizophrenia, and Wernicke-Korsakoff syndrome. The status of MT isoforms and other low molecular weight zinc-binding proteins in these conditions, diseases, disorders, or syndromes is being delineated at this time. Since several of these disorders, such as amyotrophic lateral sclerosis, are associated with oxidative stress, and since MT is able to prevent the formation of free radicals, it is believed that cytokine-induced induction of MT provides a long-lasting protection to avert oxidative damage.
大脑中许多（但并非全部）含锌神经元是谷氨酸能神经元的一个亚类，主要存在于端脑。这些神经元在其突触前终末储存锌，并通过钙依赖机制释放锌。这些锌的“囊泡”池被视为配体门控离子通道和电压门控离子通道的内源性调节剂。金属硫蛋白（MTs）是低分子量的锌结合蛋白，由25 - 30%的半胱氨酸组成，不含芳香族氨基酸或二硫键。大脑中锌含量高的区域，如视网膜、松果体和海马体，持续合成独特的MT亚型。四种MT亚型被认为为神经元和神经胶质成分提供了在突触前终末分布、捐赠和隔离锌的机制；或在突触连接处缓冲过量的锌。在这种情况下，谷胱甘肽二硫化物可能参与从MT中释放锌。相似的核苷酸和氨基酸序列使得难以获得能够明确区分MT亚型的cDNA探针和抗体。MT - I和MT - II亚型存在于大脑和外周组织中；MT - III亚型多了七个氨基酸，主要在大脑中表达，在肠道和胰腺中表达量极少；而MT - IV亚型存在于含有复层鳞状上皮细胞的组织中。由于MTs在将锌隔离于突触小泡中的神经元中表达，MT亚型表达的调节对于维持锌的稳态水平和控制氧化还原电位极为重要。锌的浓度已被证明在大量中枢神经系统疾病中发生改变，包括酒精中毒、阿尔茨海默病型痴呆、肌萎缩侧索硬化症、唐氏综合征、癫痫、弗里德赖希共济失调、格林 - 巴利综合征、肝性脑病、多发性硬化症、帕金森病、皮克病、色素性视网膜炎、视网膜营养不良、精神分裂症和韦尼克 - 科尔萨科夫综合征。目前正在研究这些病症、疾病、紊乱或综合征中MT亚型和其他低分子量锌结合蛋白的状态。由于其中一些疾病，如肌萎缩侧索硬化症，与氧化应激有关，并且由于MT能够防止自由基的形成，人们认为细胞因子诱导的MT诱导提供了长期保护以避免氧化损伤。
