Extracellular ATP inhibits chloride channels in mature mammalian skeletal muscle by activating P2Y1 receptors.
Extracellular ATP inhibits chloride channels in mature mammalian skeletal muscle by activating P2Y1 receptors.
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细胞外 ATP 通过激活 P2Y1 受体来抑制成熟哺乳动物骨骼肌中的氯离子通道。
DOI：
10.1113/jphysiol.2009.179275
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Voss,AndrewA
中科院分区：
文献类型：
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作者：
Voss,AndrewA
运动时骨骼肌会释放三磷酸腺苷，这一发现可以追溯到1969年。令人惊讶的是，很少有研究考察细胞外ATP对成熟哺乳动物骨骼肌的影响。本研究利用两个细胞内微电极研究了细胞外ATP对完全神经支配的大鼠耳提肌的作用。通过测量单个肌纤维对阶跃电流脉冲的微小终板电位(MEPP)和电压响应的相对变化来确定ATP的作用。暴露于20μm的三磷酸腺苷使MEPP下降相延长31±7.5%(±S.D.，n=3个纤维)。同时，输入电阻增加了31±2.0%，电压响应时程增加了59±3.0%。使用2和5μ的三磷酸腺苷以及神经肌肉连接的远端区域也观察到了类似的效果，表明生理上相关水平的三磷酸腺苷增强了整个肌肉纤维的电信号。细胞外三磷酸腺苷的作用可被氯离子通道阻断剂2 0 0μ三茂铁-9-羧酸和降低胞外氯离子浓度所阻断，表明三磷酸腺苷抑制氯离子通道。高亲和力的P2Y受体激动剂2-甲硫基腺苷-5‘-O-二磷酸(2MeSADP)可产生与ATP相似的作用，其EC50为160±30 nm。250nm2MeSADP的作用可被特异性的P2Y1受体抑制剂500nmMRS2179阻断，这表明ATP作用于P2Y1受体抑制氯通道。细胞外ATP对氯通道的抑制与肌肉的兴奋性和疲劳性以及肌强直的病理生理学有关。
ATP is released from skeletal muscle during exercise, a discovery dating back to 1969. Surprisingly, few studies have examined the effects of extracellular ATP on mature mammalian skeletal muscle. This electrophysiological study examined the effects of extracellular ATP on fully innervated rat levator auris longus using two intracellular microelectrodes. The effects of ATP were determined by measuring the relative changes of miniature endplate potentials (mEPPs) and voltage responses to step current pulses in individual muscle fibres. Exposure to ATP (20 μm)prolonged the mEPP falling phase by 31 ± 7.5% (values ±s.d.,n= 3 fibres). Concurrently, the input resistance increased by 31 ± 2.0% and the time course of the voltage responses increased by 59 ± 3.0%. Analogous effects were observed using 2 and 5 μmATP, and on regions distal from the neuromuscular junction, indicating that physiologically relevant levels of ATP enhanced electrical signalling over the entire muscle fibre. The effects of extracellular ATP were blocked by 200 μmanthracene‐9‐carboxylic acid, a chloride channel inhibitor, and reduced concentrations of extracellular chloride, indicating that ATP inhibited chloride channels. A high affinity agonist for P2Y receptors, 2‐methylthioadenosine‐5′‐O‐diphosphate (2MeSADP), induced similar effects to ATP with an EC50of 160 ± 30 nm. The effects of 250 nm2MeSADP were blocked by 500 nmMRS2179, a specific P2Y1receptor inhibitor, suggesting that ATP acts on P2Y1receptors to inhibit chloride channels. The inhibition of chloride channels by extracellular ATP has implications for muscle excitability and fatigue, and the pathophysiology of myotonias.