Critical role for hyperpolarization-activated cyclic nucleotide-gated channel 2 in the AIF-mediated apoptosis.
Critical role for hyperpolarization-activated cyclic nucleotide-gated channel 2 in the AIF-mediated apoptosis.
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DOI：
10.1038/emboj.2010.253
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发表时间：
2010-11-17
期刊：
影响因子：
11.4
通讯作者：
Zhivotovsky, Boris
中科院分区：
文献类型：
--
作者：
Norberg, Erik;Karlsson, Marie;Korenovska, Olga;Szydlowski, Susanne;Silberberg, Gilad;Uhlen, Per;Orrenius, Sten;Zhivotovsky, Boris
这项研究建立了HCN 2通道作为生理相关的“钙门”，介导癌症和原代神经元细胞中的凋亡诱导因子依赖性细胞死亡。细胞钙摄取是由多种离子通道介导的受控生理过程。细胞暴露于蛋白激酶C（PKC）抑制剂之一，星形孢菌素（STS）或PKC 412，可以触发Ca 2+内流，导致细胞死亡。调控这些事件的精确分子机制仍然难以捉摸。在这项研究中，我们报告，PKC抑制剂诱导长时间的钙离子进口通过超极化激活的环核苷酸门控通道2（HCN 2）在肺癌细胞和原代培养的皮层神经元，足以触发凋亡诱导因子（AIF）介导的细胞凋亡。HCN 2的下调阻止了药物诱导的Ca 2+升高和随后的凋亡。重要的是，PKC抑制剂不会导致Ca 2+进入不表达HCN通道的HEK 293细胞。然而，HCN 2的引入使它们对STS/PKC 412诱导的凋亡敏感。HCN 2的C-末端结构域内推定的PKC磷酸化位点的突变显示，Thr 549的去磷酸化对于AIF介导的凋亡所需的延长的Ca 2+进入是至关重要的。我们的研究结果证明了HCN 2通道的一个新的作用，提供证据表明它可以作为PKC抑制剂触发的细胞死亡的上游调节剂。
This study establishes HCN2 channels as physiological relevant ‘calcium gates' that mediate apoptosis-inducing factor-dependent cell death in cancer and primary neuronal cells. Cellular calcium uptake is a controlled physiological process mediated by multiple ion channels. The exposure of cells to either one of the protein kinase C (PKC) inhibitors, staurosporine (STS) or PKC412, can trigger Ca2+ influx leading to cell death. The precise molecular mechanisms regulating these events remain elusive. In this study, we report that the PKC inhibitors induce a prolonged Ca2+ import through hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) in lung carcinoma cells and in primary culture of cortical neurons, sufficient to trigger apoptosis-inducing factor (AIF)-mediated apoptosis. Downregulation of HCN2 prevented the drug-induced Ca2+ increase and subsequent apoptosis. Importantly, the PKC inhibitors did not cause Ca2+ entry into HEK293 cells, which do not express the HCN channels. However, introduction of HCN2 sensitized them to STS/PKC412-induced apoptosis. Mutagenesis of putative PKC phosphorylation sites within the C-terminal domain of HCN2 revealed that dephosphorylation of Thr549 was critical for the prolonged Ca2+ entry required for AIF-mediated apoptosis. Our findings demonstrate a novel role for the HCN2 channel by providing evidence that it can act as an upstream regulator of cell death triggered by PKC inhibitors.
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影响因子：
50.5
作者：
Monnerat, C;Henriksson, R;Raymond, E
通讯作者：
Raymond, E
DOI：
10.2741/3385
发表时间：
2009-01-01
期刊：
Frontiers in bioscience (Landmark edition)
影响因子：
--
作者：
Reyland ME
通讯作者：
Reyland ME
影响因子：
8
作者：
Gallego, MA;Joseph, B;Marchetti, P
通讯作者：
Marchetti, P
影响因子：
4.8
作者：
Zong, XG;Eckert, C;Biel, M
通讯作者：
Biel, M
DOI：
10.1084/jem.20070193
发表时间：
2007-08-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Zhu C;Wang X;Deinum J;Huang Z;Gao J;Modjtahedi N;Neagu MR;Nilsson M;Eriksson PS;Hagberg H;Luban J;Kroemer G;Blomgren K
通讯作者：
Blomgren K