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Rescue of auditory hair cells from aminoglycoside toxicity by Clostridium difficile toxin B, an inhibitor of the small GTPases Rho/Rac/Cdc42

Bodmer, Daniel and Brors, Dominik and Pak, Kwang and Gloddek, Bertrand and Ryan, Allen. (2002) Rescue of auditory hair cells from aminoglycoside toxicity by Clostridium difficile toxin B, an inhibitor of the small GTPases Rho/Rac/Cdc42. Hearing research, Vol. 172, no. 1-2. pp. 81-86.

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Official URL: http://edoc.unibas.ch/dok/A5252078

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Abstract

The hair cells (HCs) are the most vulnerable elements in the cochlea and damage to them is the most common cause of sensorineural hearing loss. Understanding the intracellular events that lead to the death of HCs is a key to developing protective strategies. Recently, it has been shown that the c-Jun-N-terminal kinase (JNK) pathway is activated in HCs in response to aminoglycosides (J. Neurosci. 20 (2000) 43). We have studied the upstream events leading to JNK activation in aminoglycoside toxicity in vitro. The small GTPases Rac and Cdc42 are well known upstream activators of JNK in other cell types. Clostridium difficile toxin B monoglucosylates all members of the Rho GTPase subfamily (Rho, Rac and Cdc42 isoforms) and inhibits GTP binding by steric interference (Nature 341 (1989) 209). Organ of Corti explants from p5 rat basal turns were maintained in tissue culture and treated with C. difficile toxin B for 12 h. They were then treated with toxin B plus gentamicin for 72 h. Significantly less HC death was observed compared to with gentamicin alone. Toxin B alone had no effect on HCs at the highest concentration used. Using antibodies against phospho-c-Jun, we observed background immunoreactivity in control explants, strong staining of outer hair cell nuclei in gentamicin treated explants, and weaker immunostaining in explants treated with gentamicin and C. difficile toxin B. We conclude that Rho family small GTPases play a role in aminoglycoside toxicity signaling as upstream activators of the JNK signaling pathway.
Faculties and Departments:03 Faculty of Medicine > Bereich Spezialf├Ącher (Klinik) > Otorhinolaryngologie > Oto-Rhino-Laryngologie (Bodmer)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Spezialf├Ącher (Klinik) > Otorhinolaryngologie > Oto-Rhino-Laryngologie (Bodmer)
UniBasel Contributors:Bodmer, Daniel K
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Elsevier
ISSN:0378-5955
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:22 Mar 2012 14:24
Deposited On:22 Mar 2012 13:38

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