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The Journal of Neuroscience, May 7, 2008, 28(19):4918-4928; doi:10.1523/JNEUROSCI.4914-07.2008

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

Manuela Lahne and Jonathan E. Gale

UCL Ear Institute and Department of Physiology, University College London, London WC1X 8EE, United Kingdom

Correspondence should be addressed to Dr. Jonathan E. Gale, UCL Ear Institute, 332 Gray's Inn Road, London WC1X 8EE, UK. Email: j.e.gale{at}ucl.ac.uk

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.

Key words: cochlea; ototoxicity; calcium signaling; purinergic receptors; cell–cell communication; ERK

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Received Oct. 31, 2007; revised Feb. 29, 2008; accepted March 28, 2008.

Correspondence should be addressed to Dr. Jonathan E. Gale, UCL Ear Institute, 332 Gray's Inn Road, London WC1X 8EE, UK. Email: j.e.gale{at}ucl.ac.uk

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