Regulation of outer hair cell electromotility and noise-induced hearing loss

Excessively loud sounds and noise are among the leading causes of deafness and hearing impair- ment in the US. Acoustic over-stimulation is likely to activate multiple physiological mechanisms, most of which are poorly understood. Perhaps the first process that would be shut down in the face of acoustic over-stimulation is the cochlear amplification of sound-induced vibrations. Frestin, a unique plasma membrane molecular motor of the outer hair cells, is critical for the cochlear amplification. Although regula- tion of important cellular functions via signaling pathways is a fundamental property of the cells, a signaling pathway that would "shut down" the operation of prestin is still unknown. Our preliminary data show that direct activation of TRPAI channels by specific agonists inhibits the motor activity of prestin in the outer hair cells. This inhibition is not observed in mice lacking the TRPA1 channels (Trpalj. Since TRFA1 could be a downstream target of a variety of second-messenger systems, TRPA1-mediated inhibition of prestin may represent a general mechanism regulating cochlear amplification during various stresses, including acoustic over-stimulation. Consistent with this idea, our preliminary data show that moderate noise exposure results in a significantly larger elevation of hearing thresholds in Trpa 1~' mice as compared to wild type (Trpaf') littermates. Although the signaling pathways that control TRPA1 in outer hair cells have yet to be identified, we found that extracellular ATP can inhibit prestin motor activity in Trpe1~ but not in TrpaV' mice. The g~j of this project is to determine how TRPA1 channels participate in the protection of the cochlea from over- stimulation. This study will test the following central hypothesis: The cochlea is protected from acoustic over-stimulation by activation of TRPA1 channels and inhibition of prestin motor activity, a previously unknown mechanism that can be activated via metabotropic ATP receptors. The proposed study will determine: 1) specific intracochlear processes that are affected by a TRPA1 deficiency; 2) the mechanism of TRPA1 activation in outer hair cells; 3)the mechanism of TRPAI-mediated inhibition of outer hair cell electromotility. Identification of the cellular processes and key molecules regulating outer hair cell electromotility at high sound intensities will open a new avenue of research in the field of noise-induced hearing loss. It may also lead to pharmacological interventions that would prevent damage of the cochlea through the enhancement of natural protection mechanisms. Finally, the genes encoding the proteins involved in this novel mechanism of cochlear regulation would represent attractive candidates to screen for genetic variants that are associated with susceptibility or resistance to noise-induced and perhaps other types of hearing loss.