Gene Knock-Outs of Inositol 1,4,5-Trisphosphate Receptors Types 1 and 2 Result in Perturbation of Cardiogenesis
Gene Knock-Outs of Inositol 1,4,5-Trisphosphate Receptors Types 1 and 2 Result in Perturbation of Cardiogenesis
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DOI：
10.1371/journal.pone.0012500
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发表时间：
2010-09
期刊：
影响因子：
3.7
通讯作者：
K. Uchida;Megumi Aramaki;Maki Nakazawa;Chihiro Yamagishi;S. Makino;K. Fukuda;Takeshi Nakamura;Takao Takahashi;K. Mikoshiba;H. Yamagishi
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文献类型：
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作者：
K. Uchida;Megumi Aramaki;Maki Nakazawa;Chihiro Yamagishi;S. Makino;K. Fukuda;Takeshi Nakamura;Takao Takahashi;K. Mikoshiba;H. Yamagishi
背景1，4，5-三磷酸肌醇受体（IP 3R 1，2和3）是细胞内钙释放通道，调节各种生命过程。虽然Ryanodine受体2型，另一种类型的细胞内Ca 2+释放通道，已被证明在胚胎心肌细胞中发挥作用，但IP 3Rs在心脏发生中的功能仍不清楚。方法/主要发现我们发现，IP 3R 1 −/−-IP 3R 2 −/−双突变小鼠在胚胎第11.5天（E）死于子宫内，心脏的心室肌和房室（AV）管发育缺陷，即使在这个发育阶段的IP 3R 1 −/−或IP 3R 2 −/−单突变小鼠中没有检测到心脏缺陷。双突变表型类似于缺乏钙调磷酸酶/NFATc信号传导的小鼠，并且NFATc在来自双敲除突变小鼠的胚胎心脏中是无活性的。IP 3R 1/R2的双重突变和IP 3Rs的药理学抑制模拟了由钙调神经磷酸酶抑制引起的AV瓣膜缺陷的表型，并且可以被组成性活性钙调神经磷酸酶挽救。结论/意义我们的研究结果表明，IP 3受体在心脏发生中的重要作用，部分通过调节钙调神经磷酸酶-NFAT信号。
Background Inositol 1,4,5-trisphosphate receptors (IP3R1, 2, and 3) are intracellular Ca2+ release channels that regulate various vital processes. Although the ryanodine receptor type 2, another type of intracellular Ca2+ release channel, has been shown to play a role in embryonic cardiomyocytes, the functions of the IP3Rs in cardiogenesis remain unclear. Methodology/Principal Findings We found that IP3R1−/−-IP3R2−/− double-mutant mice died in utero with developmental defects of the ventricular myocardium and atrioventricular (AV) canal of the heart by embryonic day (E) 11.5, even though no cardiac defect was detectable in IP3R1−/− or IP3R2−/− single-mutant mice at this developmental stage. The double-mutant phenotype resembled that of mice deficient for calcineurin/NFATc signaling, and NFATc was inactive in embryonic hearts from the double knockout-mutant mice. The double mutation of IP3R1/R2 and pharmacologic inhibition of IP3Rs mimicked the phenotype of the AV valve defect that result from the inhibition of calcineurin, and it could be rescued by constitutively active calcineurin. Conclusions/Significance Our results suggest an essential role for IP3Rs in cardiogenesis in part through the regulation of calcineurin-NFAT signaling.