Increased complexity of Tmem16a/Anoctamin 1 transcript alternative splicing.
Increased complexity of Tmem16a/Anoctamin 1 transcript alternative splicing.
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DOI：
10.1186/1471-2199-12-35
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发表时间：
2011-08-08
影响因子：
--
通讯作者：
Britton FC
中科院分区：
文献类型：
--
作者：
O'Driscoll KE;Pipe RA;Britton FC
TMEM 16 A（Anoctamin 1; ANO 1）是一种八跨膜蛋白，其功能是钙激活的氯离子通道。人类TMEM 16 A具有可变剪接的外显子（6 b、13和15），其在通道功能的调节中具有重要作用。小鼠Tmem 16 a由25个外显子组成，编码956个氨基酸的蛋白质。在这项研究中，我们的目的是提供小鼠Tmem 16 a基因组结构的细节，并调查是否Tmem 16 a转录经过选择性剪接产生通道多样性。我们鉴定了由替代外显子6 b、10、13、14、15和18组成的Tmem 16 a转录变体。我们的研究结果表明，这些外显子中的许多以各种组合表达，并且这些剪接事件在小鼠和人类之间大多是保守的。此外，我们证实了这些外显子变体在其他小鼠组织中的表达。另外的剪接事件，包括一个新的保守外显子13 b，串联剪接位点的外显子1和21和两个内含子保留事件。我们的研究结果表明，Tmem 16 a基因比以前描述的要复杂得多。复杂性在跨越外显子6至16的区域中尤其明显，其中许多选择性剪接事件被认为影响钙敏感性、电压依赖性以及该钙激活氯离子通道的激活和失活动力学。多种Tmem 16 a剪接变体的鉴定表明，选择性剪接是一种精致的机制，其在生理和病理生理条件下使TMEM 16 A通道功能多样化。
TMEM16A (Anoctamin 1; ANO1) is an eight transmembrane protein that functions as a calcium-activated chloride channel. TMEM16A in human exhibits alternatively spliced exons (6b, 13 and 15), which confer important roles in the regulation of channel function. Mouse Tmem16a is reported to consist of 25 exons that code for a 956 amino acid protein. In this study our aim was to provide details of mouse Tmem16a genomic structure and to investigate if Tmem16a transcript undergoes alternative splicing to generate channel diversity. We identified Tmem16a transcript variants consisting of alternative exons 6b, 10, 13, 14, 15 and 18. Our findings indicate that many of these exons are expressed in various combinations and that these splicing events are mostly conserved between mouse and human. In addition, we confirmed the expression of these exon variants in other mouse tissues. Additional splicing events were identified including a novel conserved exon 13b, tandem splice sites of exon 1 and 21 and two intron retention events. Our results suggest that Tmem16a gene is significantly more complex than previously described. The complexity is especially evident in the region spanning exons 6 through 16 where a number of the alternative splicing events are thought to affect calcium sensitivity, voltage dependence and the kinetics of activation and deactivation of this calcium-activated chloride channel. The identification of multiple Tmem16a splice variants suggests that alternative splicing is an exquisite mechanism that operates to diversify TMEM16A channel function in both physiological and pathophysiological conditions.
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