Involvement of ras activation in toxic hair cell damage of the mammalian cochlea

Neuroscience. 2003;122(4):1025-35. doi: 10.1016/j.neuroscience.2003.08.041.


To identify possible intracellular mediators of hair cell (HC) death due to ototoxins, we treated basal-turn, neonatal, rat HCs in vitro with several intracellular signaling inhibitors, prior to and during gentamicin exposure. The general guanine nucleotide-binding protein (G-protein) inhibitor, GDP-betaS (1 mM), provided potent HC protection, suggesting involvement of G-proteins in the intracellular pathway linking gentamicin exposure to HC death. ADP-betaS had minimal effect, indicating that the protection is specific to guanosine diphosphate (GDP)-binding, rather than a general reaction to nucleotides. Azido-GTP(32) photolabeling and gel electrophoresis indicated activation of an approximately 21 kDa G-protein in HCs after exposure to gentamicin. Spectroscopic analysis of peptide fragments from this band matched its sequence with H-Ras. The Ras inhibitors B581 (50 microM) and FTI-277 (10 microM) provided potent protection against damage and reduced c-Jun activation in HC nuclei, suggesting that activation of Ras is functionally involved in damage to these cells due to gentamicin.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cochlea / drug effects
  • Cochlea / metabolism
  • Cochlea / pathology
  • Enzyme Inhibitors / pharmacology
  • Gentamicins / toxicity*
  • Growth Inhibitors / pharmacology
  • Hair Cells, Auditory / drug effects*
  • Hair Cells, Auditory / metabolism
  • Hair Cells, Auditory / pathology
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • ras Proteins / antagonists & inhibitors
  • ras Proteins / metabolism*


  • Enzyme Inhibitors
  • Gentamicins
  • Growth Inhibitors
  • ras Proteins