Expression, Localization, and Pharmacological Role of Kv7 Potassium Channels in Skeletal Muscle Proliferation, Differentiation, and Survival after Myotoxic Insults
Expression, Localization, and Pharmacological Role of Kv7 Potassium Channels in Skeletal Muscle Proliferation, Differentiation, and Survival after Myotoxic Insults
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DOI：
10.1124/jpet.109.162800
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发表时间：
2010-03-01
影响因子：
3.5
通讯作者：
Taglialatela, Maurizio
中科院分区：
文献类型：
--
作者：
Iannotti, Fabio Arturo;Panza, Elisabetta;Taglialatela, Maurizio
钾通道表达的变化调节骨骼肌发育。本研究的目的是探讨K(V)7电压门控性钾通道在骨骼肌分化、增殖和肌毒性损伤后存活中的表达及其药理学作用。用聚合酶链式反应和/或实时定量聚合酶链式反应检测小鼠C2C12成肌细胞中所有K(V)7基因(K(V)7.1-K(V)7.5)的转录本，肌管形成后K(V)7.1、K(V)7.3和K(V)7.4的转录本表达上调。Western印迹实验证实K(V)7.2、K(V)7.3和K(V)7.4亚基在体外分化过程中均有表达，K(V)7.3和K(V)7.4亚基表达上调。在小鼠和人的成年骨骼肌中，K(V)7.2和K(V)7.3的免疫反应主要定位于强直G阳性三联体之间的细胞内纹水平，而K(V)7.4亚基的免疫反应主要局限于肌膜。在C2C12细胞中，神经元表达K(V)7.2~K(V)7.5亚基的特异性激活剂瑞格他滨(10 MU M)可抑制美伐他汀(IC50约为7 mU M)的增殖，促进肌生成素的表达，并抑制美伐他汀的肌肉毒性作用；K(V)7通道阻滞剂10，10-bis(4-pyridinylmethyl)-9(10H)-anthracenone(XE-991)(10 MU M)可阻断雷替加宾的上述作用。这些数据集中强调了神经K(V)7通道是调节骨骼肌增殖、分化和药物的肌毒性作用的重要药理靶点。
Changes in the expression of potassium channels regulate skeletal muscle development. The purpose of this study was to investigate the expression profile and pharmacological role of K(v)7 voltage-gated potassium channels in skeletal muscle differentiation, proliferation, and survival after myotoxic insults. Transcripts for all K(v)7 genes (K(v)7.1-K(v)7.5) were detected by polymerase chain reaction (PCR) and/or real-time PCR in murine C2C12 myoblasts; K(v)7.1, K(v)7.3, and K(v)7.4 transcripts were up-regulated after myotube formation. Western blot experiments confirmed K(v)7.2, K(v)7.3, and K(v)7.4 subunit expression, and the up-regulation of K(v)7.3 and K(v)7.4 subunits during in vitro differentiation. In adult skeletal muscles from mice and humans, K(v)7.2 and K(v)7.3 immunoreactivity was mainly localized at the level of intracellular striations positioned between ankyrinG-positive triads, whereas that of K(v)7.4 subunits was largely restricted to the sarcolemmal membrane. In C2C12 cells, retigabine (10 mu M), a specific activator of neuronally expressed K(v)7.2 to K(v)7.5 subunits, reduced proliferation, accelerated myogenin expression, and inhibited the myotoxic effect of mevastatin (IC50 approximate to 7 mu M); all these effects of retigabine were prevented by the K(v)7 channel blocker 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone (XE-991) (10 mu M). These data collectively highlight neural K(v)7 channels as significant pharmacological targets to regulate skeletal muscle proliferation, differentiation, and myotoxic effects of drugs.