Modulation of activator protein 1/DNA binding activity by acoustic overstimulation in the guinea-pig cochlea

Changes in gene expression are part of the homeostatic machinery with which cells respond to external stimuli or assaults. The activity of the early response transcriptional factor activator protein-1 (AP-1) can be modulated by a variety of environmental stimuli including those that alter the cellular oxidation/reduction status. This study investigates the activation of AP-1/DNA binding in the guinea-pig cochlea in response to acoustic overstimulation which produces reactive oxygen species. Electrophoretic mobility shift assays revealed that binding of AP-1 to its radiolabeled oligonucleotide probe markedly changed in nuclear extracts of inner ear tissues following intense noise exposure (4 kHz octave band, 115 dB, 5 h). AP-1/DNA binding increased in the organ of Corti and the lateral wall tissues immediately after the exposure, returning to near-baseline levels 5 h later. At 15 h after noise, a second peak of binding activity occurred in the organ of Corti whereas stria vascularis showed a lesser but more sustained activity. Binding in nuclear extracts from the spiral ganglion did not change. Incubation of nuclear extracts with antibodies against Fos/Jun family proteins prior to a supershift assay showed Fra-2 as a major component of the AP-1 complex immediately after the noise exposure. In the organ of Corti, Fra-2 immunoreactivity was localized to the middle turn, i.e. the region which is most affected by the 4-kHz octave band exposure. The results suggest the modulation of gene expression via the activation of AP-1 as a consequence of noise trauma but also demonstrate differential responses in cochlear tissues. [Copyright &y& Elsevier]