Calcium Channel CaVα₁ Splice Isoforms - Tissue Specificity and Drug Action.
Calcium Channel CaVα₁ Splice Isoforms - Tissue Specificity and Drug Action.
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DOI：
10.2174/1874467208666150507103215
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发表时间：
2015
影响因子：
2.7
通讯作者：
Andrade A
中科院分区：
文献类型：
--
作者：
Lipscombe D;Andrade A
电压门控钙离子通道对于可兴奋细胞的许多生物学功能是必不可少的，并且在治疗包括心血管和神经系统的疾病的许多疾病中，它们作为药物靶点的重要性得到了广泛的认识。每个Cacna 1基因都有可能通过选择性前mRNA剪接和使用替代启动子产生许多结构上、功能上以及在某些情况下独特的CaVα1亚基。对一系列人类组织转录组的快速出现的深度测序数据的分析包含了量化Cacna1基因的组织特异性和选择性外显子使用模式的信息。细胞核DNA和RNA结合蛋白的细胞特异性作用控制着前mRNA剪接过程中交替启动子的使用和交替外显子的选择，并且它们决定了不同类型细胞内表达的蛋白质同种型的谱。在不同组织中表达的CaV同种型之间，离散蛋白质结构域内的氨基酸组成可能存在显著差异，并且这种差异可能大于紧密相关物种的CaV通道同源物之间存在的差异。在这里，我们强调的例子，CaV亚型具有独特的表达模式，并表现出不同的药理学敏感性。CaV亚型在不同的人体组织，细胞群，年龄和疾病状态的表达模式的知识，应告知战略，旨在开发下一代CaV通道抑制剂和激动剂，提高组织特异性。
Voltage-gated calcium ion channels are essential for numerous biological functions of excitable cells and there is wide spread appreciation of their importance as drug targets in the treatment of many disorders including those of cardiovascular and nervous systems. Each Cacna1 gene has the potential to generate a number of structurally, functionally, and in some cases pharmacologically unique CaVα1 subunits through alternative pre-mRNA splicing and the use of alternate promoters. Analyses of rapidly emerging deep sequencing data for a range of human tissue transcriptomes contain information to quantify tissue-specific and alternative exon usage patterns for Cacna1 genes. Cell-specific actions of nuclear DNA and RNA binding proteins control the use of alternate promoters and the selection of alternate exons during pre-mRNA splicing, and they determine the spectrum of protein isoforms expressed within different types of cells. Amino acid compositions within discrete protein domains can differ substantially among CaV isoforms expressed in different tissues, and such differences may be greater than those that exist across CaV channel homologs of closely related species. Here we highlight examples of CaV isoforms that have unique expression patterns and that exhibit different pharmacological sensitivities. Knowledge of expression patterns of CaV isoforms in different human tissues, cell populations, ages, and disease states should inform strategies aimed at developing the next generation of CaV channel inhibitors and agonists with improved tissue-specificity.