Insights into the Pathology of the α3 Na(+)/K(+)-ATPase Ion Pump in Neurological Disorders; Lessons from Animal Models.
Insights into the Pathology of the α3 Na(+)/K(+)-ATPase Ion Pump in Neurological Disorders; Lessons from Animal Models.
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DOI：
10.3389/fphys.2016.00209
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发表时间：
2016
影响因子：
4
通讯作者：
Lykke-Hartmann K
中科院分区：
文献类型：
--
作者：
Holm TH;Lykke-Hartmann K
跨膜Na+-/K+ ATP酶位于所有哺乳动物细胞的质膜上。Na+-/K+ ATP酶利用ATP水解产生的能量将三个Na+阳离子挤出并将两个K+阳离子输入细胞。活性Na+-/K+ ATP酶的最小构象是一个α（α）和一个β（β）亚基。哺乳动物表达四种α亚型（α1−4），分别由ATP 1A 1 -4基因编码。α1亚型在成人中枢神经系统（CNS）中广泛表达，而α2主要在星形胶质细胞中表达，α3主要在神经元中表达。Na+和K+是神经元去极化过程中参与动作电位传播的主要离子。因此，α1和α3 Na+-/K+ ATP酶是在去极化后恢复神经元膜电位和维持神经元兴奋性的主要候选者。与α1相比，α3亚型的Na+亲和力约低4倍，是快速恢复[Na+]i大幅一过性升高所必需的。因此，与α3缺乏相关的疾病可能因阈上神经元活动而加重。α3亚型被认为支持神经递质的再摄取。这些过程是正常大脑活动所必需的，事实上，编码α3亚型的ATP 1A 3的常染色体显性从头突变已被发现可导致三种神经系统疾病：快速发作肌张力障碍性帕金森综合征（RDP）、儿童交替性偏瘫（AHC）、小脑共济失调、反射消失、高弓足、视神经萎缩和感觉神经性听力损失（CAPOS）。所有这三种疾病均引起神经系统症状的急性发作，但主要的神经系统表现不同，AHC的偏瘫/肌张力障碍发作和智力下降特别早发，CAPOS综合征的共济失调性脑病和视力和听力受损，RDP的肌张力障碍/帕金森综合征迟发。已经产生了几种小鼠模型来研究Atp 1a 3调节的体内后果。不同的小鼠表现出不同程度的多动，步态问题，学习障碍以及应激诱导的癫痫发作。随着几种Atp 1a 3基因或化学修饰的动物模型的出现，这些动物模型与人类疾病的许多方面密切相关，我们将能够更好地了解RDP，AHC和CAPOS综合征的病因。
The transmembrane Na+-/K+ ATPase is located at the plasma membrane of all mammalian cells. The Na+-/K+ ATPase utilizes energy from ATP hydrolysis to extrude three Na+ cations and import two K+ cations into the cell. The minimum constellation for an active Na+-/K+ ATPase is one alpha (α) and one beta (β) subunit. Mammals express four α isoforms (α1−4), encoded by the ATP1A1-4 genes, respectively. The α1 isoform is ubiquitously expressed in the adult central nervous system (CNS) whereas α2 primarily is expressed in astrocytes and α3 in neurons. Na+ and K+ are the principal ions involved in action potential propagation during neuronal depolarization. The α1 and α3 Na+-/K+ ATPases are therefore prime candidates for restoring neuronal membrane potential after depolarization and for maintaining neuronal excitability. The α3 isoform has approximately four-fold lower Na+ affinity compared to α1 and is specifically required for rapid restoration of large transient increases in [Na+]i. Conditions associated with α3 deficiency are therefore likely aggravated by suprathreshold neuronal activity. The α3 isoform been suggested to support re-uptake of neurotransmitters. These processes are required for normal brain activity, and in fact autosomal dominant de novo mutations in ATP1A3 encoding the α3 isoform has been found to cause the three neurological diseases Rapid Onset Dystonia Parkinsonism (RDP), Alternating Hemiplegia of Childhood (AHC), and Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS). All three diseases cause acute onset of neurological symptoms, but the predominant neurological manifestations differ with particularly early onset of hemiplegic/dystonic episodes and mental decline in AHC, ataxic encephalopathy and impairment of vision and hearing in CAPOS syndrome and late onset of dystonia/parkinsonism in RDP. Several mouse models have been generated to study the in vivo consequences of Atp1a3 modulation. The different mice show varying degrees of hyperactivity, gait problems, and learning disability as well as stress-induced seizures. With the advent of several Atp1a3-gene or chemically modified animal models that closely phenocopy many aspects of the human disorders, we will be able to reach a much better understanding of the etiology of RDP, AHC, and CAPOS syndrome.