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首页> 美国卫生研究院文献>The Journal of General Physiology >Highly Ca2+-selective TRPM Channels Regulate IP3-dependent Oscillatory Ca2+ Signaling in the C. elegans Intestine
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Highly Ca2+-selective TRPM Channels Regulate IP3-dependent Oscillatory Ca2+ Signaling in the C. elegans Intestine

机译：高度Ca2 +选择性TRPM通道调节线虫肠道中IP3依赖的振荡Ca2 +信号传导。

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Posterior body wall muscle contraction (pBoc) in the nematode Caenorhabditis elegans occurs rhythmically every 45–50 s and mediates defecation. pBoc is controlled by inositol-1,4,5-trisphosphate (IP3)–dependent Ca2+ oscillations in the intestine. The intestinal epithelium can be studied by patch clamp electrophysiology, Ca2+ imaging, genome-wide reverse genetic analysis, forward genetics, and molecular biology and thus provides a powerful model to develop an integrated systems level understanding of a nonexcitable cell oscillatory Ca2+ signaling pathway. Intestinal cells express an outwardly rectifying Ca2+ (ORCa) current with biophysical properties resembling those of TRPM channels. Two TRPM homologues, GON-2 and GTL-1, are expressed in the intestine. Using deletion and severe loss-of-function alleles of the gtl-1 and gon-2 genes, we demonstrate here that GON-2 and GTL-1 are both required for maintaining rhythmic pBoc and intestinal Ca2+ oscillations. Loss of GTL-l and GON-2 function inhibits IORCa ∼70% and ∼90%, respectively. IORCa is undetectable in gon-2;gtl-1 double mutant cells. These results demonstrate that (a) both gon-2 and gtl-1 are required for ORCa channel function, and (b) GON-2 and GTL-1 can function independently as ion channels, but that their functions in mediating IORCa are interdependent. IORCa, IGON-2, and IGTL-1 have nearly identical biophysical properties. Importantly, all three channels are at least 60-fold more permeable to Ca2+ than Na+. Epistasis analysis suggests that GON-2 and GTL-1 function in the IP3 signaling pathway to regulate intestinal Ca2+ oscillations. We postulate that GON-2 and GTL-1 form heteromeric ORCa channels that mediate selective Ca2+ influx and function to regulate IP3 receptor activity and possibly to refill ER Ca2+ stores.
机译：线虫秀丽隐杆线虫的后体壁肌肉收缩（pBoc）每45-50 s有节奏地发生一次，并介导排便。 pBoc受到肠道中1,4,5-三磷酸肌醇（IP3）依赖性Ca 2 + 振荡的控制。肠上皮细胞可以通过膜片钳电生理学，Ca 2 + 成像，全基因组反向遗传分析，正向遗传学和分子生物学研究，从而提供了一个强大的模型，可以发展对肿瘤的综合系统水平的了解非兴奋细胞振荡Ca 2 + 信号通路肠道细胞表达向外整流的Ca 2 + （ORCa）电流，其生物物理特性类似于TRPM通道。在肠中表达了两个TRPM同源物GON-2和GTL-1。利用gtl-1和gon-2基因的缺失和功能严重丧失的等位基因，我们证明了GON-2和GTL-1都是维持节律性pBoc和肠道Ca 2 + 振荡。 GTL-1和GON-2功能的丧失分别抑制IORCa〜70％和〜90％。在gon-2； gtl-1双重突变细胞中无法检测到IORCa。这些结果证明（a）gon-2和gtl-1都是ORCa通道功能所必需的，并且（b）GON-2和GTL-1可以独立地充当离子通道，但是它们在介导IORCa中的功能是相互依赖的。 IORCa，IGON-2和IGTL-1具有几乎相同的生物物理特性。重要的是，所有三个通道的Ca 2 + 渗透性至少是Na + 的60倍。上位性分析表明，GON-2和GTL-1在IP3信号通路中起着调节肠道Ca 2 + 振荡的作用。我们推测GON-2和GTL-1形成异源ORCa通道，介导选择性Ca 2 + 流入并起到调节IP3受体活性并可能补充ER Ca 2 + 的作用商店。

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