@article {Lahne4918, author = {Manuela Lahne and Jonathan E. Gale}, title = {Damage-Induced Activation of ERK1/2 in Cochlear Supporting Cells Is a Hair Cell Death-Promoting Signal That Depends on Extracellular ATP and Calcium}, volume = {28}, number = {19}, pages = {4918--4928}, year = {2008}, doi = {10.1523/JNEUROSCI.4914-07.2008}, publisher = {Society for Neuroscience}, abstract = {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{\textquoteright} and phalangeal cells but not in hair cells. The activation of ERK1/2 spread along the length of the cochlea, reaching its peak 5{\textendash}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.}, issn = {0270-6474}, URL = {https://www.jneurosci.org/content/28/19/4918}, eprint = {https://www.jneurosci.org/content/28/19/4918.full.pdf}, journal = {Journal of Neuroscience} }