Sustained currents through ASIC3 ion channels at the modest pH changes that occur during myocardial ischemia
Sustained currents through ASIC3 ion channels at the modest pH changes that occur during myocardial ischemia
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DOI：
10.1161/01.res.0000238388.79295.4c
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发表时间：
2006-09-01
影响因子：
20.1
通讯作者：
McCleskey, Edwin W.
中科院分区：
文献类型：
--
作者：
Yagi, Junichi;Wenk, Heather N.;McCleskey, Edwin W.
酸敏感离子通道3（ASIC 3）在神经支配心脏和骨骼肌的感觉神经元上高度表达，并且因此被提出用于检测乳酸性酸中毒以及预防心绞痛和肌肉缺血性疼痛。这个想法的一个困难是，ASIC 3迅速脱敏。脱敏离子通道如何介导持续的感觉，如心绞痛？在这里，我们表明，大鼠ASIC 3产生持续的电流在有限的范围内的细胞外pH值（7.3至6.7），发生在心脏和骨骼肌缺血;实验使用膜片钳转染细胞系和荧光标记的感觉神经元，支配大鼠心脏。ASIC 1a（无论是同聚体还是1a/3异聚体）都不会产生这样的持续电流，而ASIC 2a/3异聚体产生的电流比ASIC 3同聚体大得多。持续的电流甚至持续数十分钟，因为它是由通道的失活和激活之间存在重叠的pH区域引起的。乳酸盐，厌氧代谢产物，允许电流激活在稍微碱性pH值。令人惊讶的是，阿米洛利，它阻止ASIC时，他们在较低的pH值激活，增加ASIC 3电流诱发pH 7.0。心脏感觉神经元表现出一个小的，完美的持续电流时，pH值从7.4到7.0的变化。该电流中的至少一部分由ASIC承载，因为电流被Zn 2+（ASIC调节剂）和阿米洛利两者增加。我们认为这种持续模式是触发心绞痛和其他缺血性疼痛的ASIC 3门控的最相关形式。
Acid-sensing ion channel 3 (ASIC3) is highly expressed on sensory neurons that innervate heart and skeletal muscle and, therefore, is proposed to detect lactic acidosis and to transduce angina and muscle ischemic pain. A difficulty with this idea is that ASIC3 rapidly desensitizes. How can a desensitizing ion channel mediate a persisting sensation such as angina? Here, we show that rat ASIC3 produces a sustained current within the limited range of extracellular pH (7.3 to 6.7) that occurs during cardiac and skeletal muscle ischemia; experiments use patch clamp on transfected cell lines and on fluorescently tagged sensory neurons that innervate rat heart. No such sustained current occurs with ASIC1a ( either as homomers or 1a/3 heteromers), whereas ASIC2a/3 heteromers give much larger currents than ASIC3 homomers. The sustained current persists even over tens of minutes because it is caused by a region of pH where there is overlap between inactivation and activation of the channel. Lactate, an anaerobic metabolite, allows the current to activate at slightly more basic pH. Surprisingly, amiloride, which blocks ASICs when they are activated at lower pH, increases ASIC3 current evoked at pH 7.0. Cardiac sensory neurons exhibit a small, perfectly sustained current when pH changes from 7.4 to 7.0. At least some of this current is carried by ASICs because the current is increased by both Zn2+, an ASIC modulator, and amiloride. We suggest that this sustained mode is the most relevant form of ASIC3 gating for triggering angina and other ischemic pain.