Novel isoforms of the sodium channels Nav1.8 and Nav1.5 are produced by a conserved mechanism in mouse and rat.
Novel isoforms of the sodium channels Nav1.8 and Nav1.5 are produced by a conserved mechanism in mouse and rat.
复制标题
钠通道NAV1.8和NAV1.5的新型同工型是通过小鼠和大鼠中的保守机理产生的。
DOI：
10.1074/jbc.m401281200
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发表时间：
2004-06-04
期刊：
影响因子：
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通讯作者：
Wynick D
中科院分区：
文献类型：
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作者：
Kerr NC;Holmes FE;Wynick D
电压门控钠通道Nav1.8仅在背根神经节、三叉神经节和结状神经节的神经元亚群中表达。我们已经分离到了跨越外显子17序列的小鼠部分长度Nav1.8 cDNA克隆，它与已发表的序列有17个核苷酸替换和12个预测的氨基酸差异。通过对跨越Scn10a的外显子16-18的4.1kb的基因组DNA进行测序，证实了相互排斥的替代外显子17的缺失。发现了一种新的cDNA1.8c，命名为Nav1.8c，它是在CAG/CAG基序上选择3‘-剪接位点，以排除跨域胞质环IDII/III中谷氨酰胺1031密码子的结果。在成年DRG、三叉神经节和新生DRG中，Nav1.8c(跳过CAG)和Nav1.8(包括CAG)的比例为~2：1。大鼠背根神经节中也存在Nav1.8c亚型，但不太常见。在另外两个河豚毒素抗性通道中，没有检测到小鼠Nav1.9的类似选择性剪接，而在CAG/CAG基序上罕见的NaV1.5选择性剪接导致了CAG三核苷酸的引入。该异构体命名为Nav1.5c，在大鼠体内保守，编码一个额外的谷氨酰胺残基，破坏推测的CK2磷酸化位点。综上所述，Nav1.8和NaV1.5的新亚型都是通过在CAG/CAG基序上交替剪接而产生的，这导致在结构域间胞质环IDII/III中没有或存在预测的谷氨酰胺残基。该胞质环中的钠通道的突变已经被证明改变了电生理特性，并导致心律失常和癫痫。
The voltage-gated sodium channel Nav1.8 is only expressed in subsets of neurons in dorsal root ganglia (DRG) and trigeminal and nodose ganglia. We have isolated mouse partial length Nav1.8 cDNA clones spanning the exon 17 sequence, which have 17 nucleotide substitutions and 12 predicted amino acid differences from the published sequence. The absence of a mutually exclusive alternative exon 17 was confirmed by sequencing 4.1 kilobases of genomic DNA spanning exons 16–18 of Scn10a. A novel cDNA isoform was identified, designated Nav1.8c, which results from alternative 3′-splice site selection at a CAG/CAG motif to exclude the codon for glutamine 1031 within the interdomain cytoplasmic loop IDII/III. The ratio of Nav1.8c (CAG-skipped) to Nav1.8 (CAG-inclusive) mRNA in mouse is ~2:1 in adult DRG, trigeminal ganglion, and neonatal DRG. A Nav1.8c isoform also occurs in rat DRG, but is less common. Of the two other tetrodotoxin-resistant channels, no analogous alternative splicing of mouse Nav1.9 was detected, whereas rare alternative splicing of Nav1.5 at a CAG/CAG motif resulted in the introduction of a CAG trinucleotide. This isoform, designated Nav1.5c, is conserved in rat and encodes an additional glutamine residue that disrupts a putative CK2 phosphorylation site. In summary, novel isoforms of Nav1.8 and Nav1.5 are each generated by alternative splicing at CAG/CAG motifs, which result in the absence or presence of predicted glutamine residues within the interdomain cytoplasmic loop IDII/III. Mutations of sodium channels within this cytoplasmic loop have previously been demonstrated to alter electrophysiological properties and cause cardiac arrhythmias and epilepsy.