Tamoxifen inhibition of kv7.2/kv7.3 channels.
Tamoxifen inhibition of kv7.2/kv7.3 channels.
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DOI：
10.1371/journal.pone.0076085
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Sanchez-Chapula JA
中科院分区：
文献类型：
--
作者：
Ferrer T;Aréchiga-Figueroa IA;Shapiro MS;Tristani-Firouzi M;Sanchez-Chapula JA
KCNQ基因编码5个Kv 7钾通道亚基（Kv7.1-Kv7.5）。其中四种（Kv7.2-Kv7.5）在神经系统中表达。Kv7.2和Kv7.3是调节神经元兴奋性的慢电压门控M通道的主要分子组分。在这项研究中，我们证明，他莫昔芬，用于治疗乳腺癌的雌激素受体拮抗剂，抑制Kv7.2/Kv7.3电流在人胚肾HEK-293细胞异源表达。三苯氧胺的电流抑制是电压依赖性的，但浓度依赖性。电流抑制的IC 50为1.68 ± 0.44 µM。通道的电压依赖性激活未被修改。他莫昔芬抑制Kv7.2同源通道的效力更高（IC 50 = 0.74 ± 0.16 µM）。突变Kv7.2 R463 E增加磷脂酰肌醇-4，5-二磷酸（PIP 2）-通道的相互作用，并显着减少他莫昔芬的抑制作用相比，野生型Kv7.2。相反，突变Kv7.2 R463 Q，减少PIP 2通道的相互作用，增加他莫昔芬的效力。与Kv7.2/Kv7.3 WT相比，在异聚体Kv7.2 R463 Q/Kv7.3和Kv7.2 R463 E/Kv7.3通道上获得了类似的结果。过表达2A型PI（4）P5激酶（PIP 5 K 2A）可显著降低他莫昔芬对Kv7.2/Kv7.3和Kv7.2 R463 Q通道的抑制作用。我们的研究结果表明，他莫昔芬抑制Kv7.2/Kv7.3通道干扰PIP 2通道的相互作用，因为它的记录与PIP 2和他莫昔芬对各种PIP 2敏感通道的类似效果。
KCNQ genes encode five Kv7 K+ channel subunits (Kv7.1–Kv7.5). Four of these (Kv7.2–Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which regulates neuronal excitability. In this study, we demonstrate that tamoxifen, an estrogen receptor antagonist used in the treatment of breast cancer, inhibits Kv7.2/Kv7.3 currents heterologously expressed in human embryonic kidney HEK-293 cells. Current inhibition by tamoxifen was voltage independent but concentration-dependent. The IC50 for current inhibition was 1.68 ± 0.44 µM. The voltage-dependent activation of the channel was not modified. Tamoxifen inhibited Kv7.2 homomeric channels with a higher potency (IC50 = 0.74 ± 0.16 µM). The mutation Kv7.2 R463E increases phosphatidylinositol- 4,5-bisphosphate (PIP2) - channel interaction and diminished dramatically the inhibitory effect of tamoxifen compared with that for wild type Kv7.2. Conversely, the mutation Kv7.2 R463Q, which decreases PIP2 -channel interaction, increased tamoxifen potency. Similar results were obtained on the heteromeric Kv7.2 R463Q/Kv7.3 and Kv7.2 R463E/Kv7.3 channels, compared to Kv7.2/Kv7.3 WT. Overexpression of type 2A PI(4)P5-kinase (PIP5K 2A) significantly reduced tamoxifen inhibition of Kv7.2/Kv7.3 and Kv7.2 R463Q channels. Our results suggest that tamoxifen inhibited Kv7.2/Kv7.3 channels by interfering with PIP2-channel interaction because of its documented interaction with PIP2 and the similar effect of tamoxifen on various PIP2 sensitive channels.
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对磷脂酰肌醇 4,5-二磷酸的亲和力决定了 Kv7 K+ 通道的毒蕈碱激动剂敏感性。
DOI：
10.1085/jgp.200910313
发表时间：
2009-11
期刊：
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影响因子：
--
作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
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发表时间：
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影响因子：
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作者：
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影响因子：
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作者：
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影响因子：
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