Alternative splicing of the sodium channel SCN8A predicts a truncated two-domain protein in fetal brain and non-neuronal cells
Alternative splicing of the sodium channel SCN8A predicts a truncated two-domain protein in fetal brain and non-neuronal cells
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DOI：
10.1074/jbc.272.38.24008
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发表时间：
1997-09-19
影响因子：
4.8
通讯作者：
Meisler, MH
中科院分区：
文献类型：
--
作者：
Plummer, NW;McBurney, MW;Meisler, MH
电压门控钠通道α亚基SCN 8A是脑和脊髓神经元中最丰富的钠通道之一。我们已经确定了两个选择性剪接外显子，18 N和18 A，编码跨膜段S3和S4的结构域III。外显子18 N在胎儿脑和非神经元组织中表达。具有外显子18 N的转录物具有保守的框内终止密码子，其预测类似于肌肉钙通道的胎儿形式的截短的双结构域蛋白质的合成。在E12.5和P1.5之间的小鼠胎脑中，含有外显子18 N的转录物的比例最高;在以后的年龄，含有外显子18 A的转录物占主导地位。在视黄酸诱导的神经元分化过程中，这种发育程序在P19细胞中重演。非神经元组织含有低水平的SCN 8A转录本，其含有外显子18 N。因此，SCN 8A提供了一种新的分化特异性剪接模型。人、小鼠和鱼的SCN 8A的基因组分析显示了一个保守的结构，其中外显子18 N位于外显子18 A上游300-500 bp。因此，外显子18的复制先于鱼类和哺乳动物的分化。外显子18 N和18 A的基因组组织、发育调控和编码内容与先前描述的神经元钠通道基因的交替外显子5 N和5A非常相似。我们的建议，外显子18 N和18 A的进化起源是由外显子5 N和5A的复制是一致的其他证据，四域阳离子通道从一个单一的域祖先通道的两轮复制。
The voltage gated sodium channel alpha subunit SCN8A is one of the most abundant sodium channels in neurons from brain and spinal cord. We have identified two alternatively spliced exons, 18N and 18A, that encode transmembrane segments S3 and S4 in domain III. Exon 18N is expressed in fetal brain and non-neuronal tissues. Transcripts with exon 18N have a conserved in-frame stop codon that predicts the synthesis of a truncated, two-domain protein similar to the fetal form of the muscle calcium channel. The proportion of transcripts containing exon 18N is highest in mouse fetal brain between E12.5 and P1.5; at later ages transcripts containing exon 18A predominate. This developmental program is recapitulated in P19 cells during retinoic acid-induced neuronal differentiation. Non-neuronal tissues contain a low level of SCN8A transcripts containing exon 18N. SCN8A thus provides a new model of differentiation specific splicing. Genomic analysis of SCN8A from human, mouse, and fish demonstrated a conserved structure in which exon 18N is located 300-500 bp upstream of exon 18A. Duplication of exon 18 thus preceded the divergence of fish and mammals. The genomic organization, developmental regulation, and coding content of exons 18N and 18A closely resemble the previously described alternate exons 5N and 5A of the neuronal sodium channel genes. Our proposal that the evolutionary origin of exons 18N and 18A was by duplication of exons 5N and 5A is consistent with other evidence that the four-domain cation channels arose by two rounds of duplication from a single-domain ancestral channel.