Profiling the array of Cav3.1 variants from the human T-type calcium channel gene CACNA1G:: Alternative structures, developmental expression, and biophysical variations
Profiling the array of Cav3.1 variants from the human T-type calcium channel gene CACNA1G:: Alternative structures, developmental expression, and biophysical variations
复制标题
DOI：
10.1002/prot.20877
复制
发表时间：
2006-08-01
影响因子：
2.9
通讯作者：
Agnew, William S.
中科院分区：
文献类型：
--
作者：
Emerick, Mark C.;Stein, Rebecca;Agnew, William S.
我们描述了CACNA 1G的调节转录组，CACNA 1G是T型Ca（v）3.1钙通道的人类基因，受到广泛的选择性RNA剪接。15个转录变异位点包括2个5 '-UTR启动子位点、2个T-UTR多聚腺苷酸化位点和11个开放阅读框内的可变剪接位点。对1580个胎儿和成人大脑全长互补DNA的调查揭示了一个由30种不同转录物组成的家族，包括随着发育而表达不同的多种功能形式。胎儿和成人转录群体的统计分析揭示了分子内剪接位点构型之间的联系模式，随着发展而发生显着变化。从胎儿转录本中几乎独立的、有偏见的剪接到成人转录本中强烈协调的剪接的转变表明，在分化细胞中重组分子结构的剪接调节的多个“程序”的进行性激活。膜片钳研究九个选定的变体有助于剪接调控的门控参数的排列最有可能修改T通道生理表达神经元。门控行为反映了可变结构域之间的组合相互作用，使分子表型依赖于合奏的共同选择的结构域，一致的发展过程中观察到的协同剪接的出现。我们的结论是，结构基因和网络的剪接调控因子定义了一个综合系统的表型变化的Ca（v）3.1生物物理学在神经系统发育。
We describe the regulated transcriptome of CACNA1G, a human gene for T-type Ca(v)3.1 calcium channels that is subject to extensive alternative RNA splicing. Fifteen sites of transcript variation include 2 alternative 5'-UTR promoter sites, 2 alternative T-UTR polyadenylation sites, and 11 sites of alternative splicing within the open reading frame. A survey of 1580 fetal and adult human brain full-length complementary DNAs reveals a family of 30 distinct transcripts, including multiple functional forms that vary in expression with development. Statistical analyses of fetal and adult transcript populations reveal patterns of linkages among intramolecular splice site configurations that change dramatically with development. A shift from nearly independent, biased splicing in fetal transcripts to strongly concerted splicing in adult transcripts suggests progressive activation of multiple "programs" of splicing regulation that reorganize molecular structures in differentiating cells. Patch-clamp studies of nine selected variants help relate splicing regulation to permutations of the gating parameters most likely to modify T-channel physiology in expressing neurons. Gating behavior reflects combinatorial interactions between variable domains so that molecular phenotype depends on ensembles of coselected domains, consistent with the observed emergence of concerted splicing during development. We conclude that the structural gene and networks of splicing regulatory factors define an integrated system for the phenotypic variation of Ca(v)3.1 biophysics during nervous system development.