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Damage-Induced Activation of ERK1/2 in Cochlear Supporting Cells Is a Hair Cell Death-Promoting Signal That Depends on Extracellular ATP and Calcium

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.