Traumatic noise activates Rho-family GTPases through transient cellular energy depletion
Small GTPases mediate transmembrane signaling and regulate the actin cytoskeleton in eukaryotic cells. Here, we characterize the auditory pathology of adult male CBA/J mice exposed to traumatic noise (2-20 kHz; 106 dB; 2 h). Loss of outer hair cells was evident 1 h after noise exposure in the basal...
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Published in | The Journal of neuroscience Vol. 32; no. 36; pp. 12421 - 12430 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
United States
Society for Neuroscience
05.09.2012
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Subjects | |
Online Access | Get full text |
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Summary: | Small GTPases mediate transmembrane signaling and regulate the actin cytoskeleton in eukaryotic cells. Here, we characterize the auditory pathology of adult male CBA/J mice exposed to traumatic noise (2-20 kHz; 106 dB; 2 h). Loss of outer hair cells was evident 1 h after noise exposure in the basal region of the cochlea and spread apically with time, leading to permanent threshold shifts of 35, 60, and 65 dB at 8, 16, and 32 kHz. Several biochemical and molecular changes correlated temporally with the loss of cells. Immediately after exposure, the concentration of ATP decreased in cochlear tissue and reached a minimum after 1 h while the immunofluorescent signal for p-AMPKα significantly increased in sensory hair cells at that time. Levels of active Rac1 increased, whereas those of active RhoA decreased significantly 1 h after noise attaining a plateau at 1-3 h; the formation of a RhoA-p140mDia complex was consistent with an activation of Rho GTPase pathways. Also at 1-3 h after exposure, the caspase-independent cell death marker, Endo G, translocated to the nuclei of outer hair cells. Finally, experiments with the inner ear HEI-OC1 cell line demonstrated that the energy-depleting agent oligomycin enhanced both Rac1 activity and cell death. The sum of the results suggests that traumatic noise induces transient cellular ATP depletion and activates Rho GTPase pathways, leading to death of outer hair cells in the cochlea. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author contributions: S.-H.S. designed research; F.-Q.C., H.-W.Z., K.H., and S.-H.S. performed research; F.-Q.C., H.-W.Z., K.H., and S.-H.S. analyzed data; S.-H.S. wrote the paper. F.-Q. Chen's present address: Department of Otolaryngology-Head and Neck Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. |
ISSN: | 0270-6474 1529-2401 1529-2401 |
DOI: | 10.1523/jneurosci.6381-11.2012 |