Aristolochic acid, a plant extract used in the treatment of pain and linked to Balkan endemic nephropathy, is a regulator of K2P channels.
Aristolochic acid, a plant extract used in the treatment of pain and linked to Balkan endemic nephropathy, is a regulator of K2P channels.
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DOI：
10.1111/bph.13465
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发表时间：
2016-05
影响因子：
7.3
通讯作者：
Mathie A
中科院分区：
文献类型：
--
作者：
Veale EL;Mathie A
马兜铃酸（AristA）是在传统药物中用于治疗疼痛的植物中发现的。我们研究了马兜铃对TREK和TRESK钾（K2P）通道的作用，这两个通道是疼痛的潜在治疗靶点。巴尔干地方性肾病（BEN）是一种与阿里斯塔消费相关的肾脏疾病。在一些BEN易感患者中发现TASK‐2 （K2P5.1）通道（T108P）突变，因此我们研究了这种突变和AristA如何影响TASK‐2通道。在存在和不存在AristA的情况下，通过野生型和突变的tsA201细胞中表达的人类K2P通道的电流使用全细胞膜片钳记录进行测量。爱丽斯塔（100 μM）可增强TREK‐1‐和TREK‐2‐介导的电流，而抑制TRESK。TRESK的抑制并不依赖于关键细胞内丝氨酸的磷酸化，而是被内孔中大量残基的突变完全阻断（F145A_F352A）。TASK‐2_T108P突变显著降低了电流密度和离子选择性。一个相关的突变（T108C）也有类似但不太明显的影响。外部碱化和氟芬那酸的应用增强了TASK‐2和TASK‐2_T108C电流，但不影响TASK‐2_T108P电流。AristA （300 μM）可适度增强TASK‐2电流。枸橼酸对TREK‐1和TREK‐2的增强和对TRESK的抑制可能有助于该化合物对疼痛的治疗作用。虽然在BEN中，AristA不太可能与TASK‐2通道直接相互作用，但TASK‐2通道功能的丧失可能间接增加对AristA毒性的易感性。
Aristolochic acid (AristA) is found in plants used in traditional medicines to treat pain. We investigated the action of AristA on TREK and TRESK, potassium (K2P) channels, which are potential therapeutic targets in pain. Balkan endemic nephropathy (BEN) is a renal disease associated with AristA consumption. A mutation of TASK‐2 (K2P5.1) channels (T108P) is seen in some patients susceptible to BEN, so we investigated how both this mutation and AristA affected TASK‐2 channels. Currents through wild‐type and mutated human K2P channels expressed in tsA201 cells were measured using whole‐cell patch‐clamp recordings in the presence and absence of AristA. TREK‐1‐ and TREK‐2‐mediated currents were enhanced by AristA (100 μM), whereas TRESK was inhibited. Inhibition of TRESK did not depend on the phosphorylation of key intracellular serines but was completely blocked by mutation of bulky residues in the inner pore (F145A_F352A). The TASK‐2_T108P mutation markedly reduced both current density and ion selectivity. A related mutation (T108C) had similar but less marked effects. External alkalization and application of flufenamic acid enhanced TASK‐2 and TASK‐2_T108C current but did not affect TASK‐2_T108P current. AristA (300 μM) produced a modest enhancement of TASK‐2 current. Enhancement of TREK‐1 and TREK‐2 and inhibition of TRESK by AristA may contribute to therapeutically useful effects of this compound in pain. Whilst AristA is unlikely to interact directly with TASK‐2 channels in BEN, loss of functional TASK‐2 channels may indirectly increase susceptibility to AristA toxicity.