Tamoxifen Inhibits Cardiac ATP-Sensitive and Acetylcholine-Activated K+ Currents in Part by Interfering With Phosphatidylinositol 4,5-Bisphosphate-Channel Interaction
Tamoxifen Inhibits Cardiac ATP-Sensitive and Acetylcholine-Activated K+ Currents in Part by Interfering With Phosphatidylinositol 4,5-Bisphosphate-Channel Interaction
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DOI：
10.1254/jphs.10024fp
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发表时间：
2010-05-01
影响因子：
3.5
通讯作者：
Sanchez-Chapula, Jose A.
中科院分区：
文献类型：
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作者：
Ponce-Balbuena, Daniela;Moreno-Galindo, Eloy G.;Sanchez-Chapula, Jose A.
他莫昔芬通过干扰Kir2.x内向整流钾通道与膜磷脂酰肌醇4，5-二磷酸(PIP2)的相互作用来抑制该通道的跨膜电流。我们测试了对PIP2低亲和力的KIR通道，如三磷酸腺苷(ATP)敏感的K+通道(K-ATP)和乙酰胆碱(ACh)激活的K+通道(K-ACh)，对他莫昔芬的敏感性至少与Kir2.3相同。本文观察了三苯氧胺(0.1-10mU M)对HEK-293细胞Kir6.2/SUR2A(K-ATP)和Kir3.1/3.4(K-ACh)通道及猫心房肌细胞ATP敏感性钾电流(I-KATP)和乙酰胆碱酯酶激活钾电流(IKACh)的影响。I-KATP和IKACh对他莫昔芬的抑制起效较慢(T-1/2约3.5min)，且呈浓度依赖性，但不依赖于电压。抑制作用的时程和程度与外用或内服药物无关。他莫昔芬与孔道形成亚基Kir6.2相互作用，而不是与Sur亚基相互作用。他莫昔芬对Kir6.2/SUR2A通道的抑制作用因Kir6.2上的突变(C166S)和PIP2的持续存在而降低。在心房肌细胞中，他莫昔芬对K-ATP和K-ACh通道的作用机制和作用强度与HEK-293细胞相似。这些数据表明，与其对Kir2.x电流的影响类似，他莫昔芬通过干扰通道与PIP2之间的相互作用来抑制K-ATP和K-ACh电流。
Tamoxifen inhibits transmembrane currents of the Kir2.x inward rectifier potassium channels by interfering with the interaction of the channels with membrane phosphatidylinositol 4,5-bisphosphate (PIP2). We tested the hypothesis that Kir channels with low affinity for PIP2, like the adenosine triphosphate (ATP)-sensitive K+ channel (K-ATP) and acetylcholine (ACh)-activated K+ channel (K-ACh), have at least the same sensitivity to tamoxifen as Kir2.3. We investigated the effects of tamoxifen (0.1 - 10 mu M) on Kir6.2/SUR2A (K-ATP) and Kir3.1/3.4 (K-ACh) channels expressed in HEK-293 cells and ATP-sensitive K+ current (I-KATP) and ACh-activated K+ current (IKACh) in feline atrial myocytes. The onset of tamoxifen inhibition of both I-KATP and IKACh was slow (T-1/2 approximately 3.5 min) and concentration-dependent but voltage-independent. The time course and degree of inhibition was independent of external or internal drug application. Tamoxifen interacts with the pore forming subunit, Kir6.2, rather than with the SUR subunit. The inhibitory potency of tamoxifen on the Kir6.2/SUR2A channel was decreased by the mutation (C166S) on Kir6.2 and in the continuous presence of PIP2. In atrial myocytes, the mechanism and potency of the effects of tamoxifen on K-ATP and K-ACh channels were comparable to those in HEK-293 cells. These data suggest that, similar to its effects on Kir2.x currents, tamoxifen inhibits K-ATP and K-ACh currents by interfering with the interaction between the channel and PIP2.