Atp8a1 deficiency is associated with phosphatidylserine externalization in hippocampus and delayed hippocampus-dependent learning.
Atp8a1 deficiency is associated with phosphatidylserine externalization in hippocampus and delayed hippocampus-dependent learning.
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DOI：
10.1111/j.1471-4159.2011.07543.x
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发表时间：
2012-01
影响因子：
4.7
通讯作者：
Banerjee P
中科院分区：
文献类型：
--
作者：
Levano K;Punia V;Raghunath M;Debata PR;Curcio GM;Mogha A;Purkayastha S;McCloskey D;Fata J;Banerjee P
负责酶活性质膜（PM）氨基磷脂移位酶（PM-APLT）的分子，催化磷脂酰丝氨酸（PS）从质膜的外叶到内叶的移位，在哺乳动物中是未知的。秀丽隐杆线虫的研究表明，哺乳动物P型ATP酶Atp 8a 1的直系同源物达特-1的消融导致生殖细胞中的PS外化。我们在这里证明，海马细胞的齿状回（DG），和角Ammonis（CA 1，CA 3）在缺乏Atp 8a 1的小鼠表现出显着增加PS外化。虽然它们的大脑皮层没有表现出异常的形态或高度的细胞凋亡，但这些小鼠表现出活动增加和大脑皮层依赖性学习的明显缺陷，但没有过度焦虑。这些观察结果表明，Atp 8a 1在神经元细胞中的PM-APLT活性中起着至关重要的作用。在确证，异位表达Atp 8a 1，但不是其密切的同源物，Atp 8a 2，导致增加的人口（Vmax）的PM-APLT没有任何变化，其签名参数Km在神经元N18细胞。相反，Atp 8a 1的P型磷酸化位点突变体（Atp 8a 1 *）的表达引起PM-APLT的Vmax降低，而不显著改变其Km。表达ATp 8a 1 * 的N18细胞也表现出PS外化而无凋亡。总之，我们的数据强烈表明，Atp 8a 1在一些哺乳动物细胞，如神经元N18和海马细胞的PM-APLT活性中起着核心作用。
The molecule responsible for the enzyme activity plasma membrane (PM) aminophospholipid translocase (PM-APLT), which catalyzes phosphatidylserine (PS) translocation from the outer to the inner leaflet of the plasma membrane, is unknown in mammals. A C.elegans study has shown that ablation of Tat-1, which is an ortholog of a mammalian P-type ATPase, Atp8a1, causes PS externalization in the germ cells. We demonstrate here that the hippocampal cells of the dentate gyrus (DG), and Cornu Ammonis (CA1, CA3) in mice lacking Atp8a1 exhibit a dramatic increase in PS externalization. Although their hippocampi showed no abnormal morphology or heightened apoptosis, these mice displayed increased activity and a marked deficiency in hippocampus-dependent learning, but no hyper-anxiety. Such observations indicate that Atp8a1 plays a crucial role in PM-APLT activity in the neuronal cells. In corroboration, ectopic expression of Atp8a1 but not its close homolog, Atp8a2, caused an increase in the population (Vmax) of PM-APLT without any change in its signature parameter Km in the neuronal N18 cells. Conversely, expression of a P-type phosphorylation-site mutant of Atp8a1 (Atp8a1*) caused a decrease in Vmax of PM-APLT without significantly altering its Km. The ATp8a1*-expressing N18 cells also exhibited PS externalization without apoptosis. Together, our data strongly indicate that Atp8a1 plays a central role in the PM-APLT activity of some mammalian cells, such as the neuronal N18 and hippocampal cells.
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