Damage-induced activation of ERK1/2 in cochlear supporting cells is a hair cell death-promoting signal that depends on extracellular ATP and calcium
Damage-induced activation of ERK1/2 in cochlear supporting cells is a hair cell death-promoting signal that depends on extracellular ATP and calcium
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DOI：
10.1523/jneurosci.4914-07.2008
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发表时间：
2008-05-07
影响因子：
5.3
通讯作者：
Gale, Jonathan E.
中科院分区：
文献类型：
--
作者：
Lahne, Manuela;Gale, Jonathan E.
声过度刺激和耳毒性药物可导致耳蜗毛细胞损伤和死亡，从而导致永久性听力损失。关于由这种创伤引发的信号通路知之甚少，尽管已经描述了c-Jun N-末端激酶[有丝分裂原活化蛋白激酶（MAPK）之一]通路的重要作用。我们研究了另一个MAPK家族，细胞外调节激酶1和2（ERK 1/2）在新生儿耳蜗外植毛细胞损伤中的作用。在外植体受到机械损伤的几分钟内，ERK 1/2在Deiters和指骨细胞中被瞬时激活，但在毛细胞中没有。ERK 1/2的激活沿着耳蜗的长度分布，在损伤开始后5-10 min达到高峰。细胞外ATP的释放和功能性连接蛋白的存在对ERK 1/2的激活和扩散至关重要。损伤后的第一秒内引起毛细胞区域的细胞间Ca 2+波。在缺乏Ca ~（2+）内流的情况下，细胞间Ca ~（2+）波和ERK 1/2激活的幅度和范围减少。用氨基糖苷类新霉素处理在固缩毛细胞周围的支持细胞中产生了类似的ERK 1/2激活模式。当ERK 1/2激活被阻止时，固缩毛细胞的数量减少。因此，体外耳蜗支持细胞中ERK 1/2的激活是一种常见的损伤信号传导机制，其作用是促进毛细胞死亡，表明支持细胞在调节毛细胞死亡中的直接作用。
Acoustic overstimulation and ototoxic drugs can cause permanent hearing loss as a result of the damage and death of cochlear hair cells. Relatively little is known about the signaling pathways triggered by such trauma, although a significant role has been described for the c-Jun N-terminal kinase [one of the mitogen-activated protein kinases (MAPKs)] pathway. We investigated the role of another MAPK family, the extracellularly regulated kinases 1 and 2 (ERK1/2) during hair cell damage in neonatal cochlear explants. Within minutes of subjecting explants to mechanical damage, ERK1/2 were transiently activated in Deiters' and phalangeal cells but not in hair cells. The activation of ERK1/2 spread along the length of the cochlea, reaching its peak 5-10 min after damage onset. Release of extracellular ATP and the presence of functional connexin proteins were critical for the activation and spread of ERK1/2. Damage elicited an intercellular Ca2+ wave in the hair cell region in the first seconds after damage. In the absence of Ca2+ influx, the intercellular Ca2+ wave and the magnitude and spread of ERK1/2 activation were reduced. Treatment with the aminoglycoside neomycin produced a similar pattern of ERK1/2 activation in supporting cells surrounding pyknotic hair cells. When ERK1/2 activation was prevented, there was a reduction in the number of pyknotic hair cells. Thus, activation of ERK1/2 in cochlear supporting cells in vitro is a common damage signaling mechanism that acts to promote hair cell death, indicating a direct role for supporting cells in regulating hair cell death.