TRPA-1 mediated protection against noise-induced hearing loss

A central process in the cochlea is the amplification of sound-induced vibrations. Prestin, a unique plasma membrane molecular motor of the outer hair cells, is essential for this amplification. Although regulation of important cellular functions via signalling pathways is a fundamental property of the cells, a signalling pathway that would "shut down" the operation of prestin is still unknown. Our preliminary data show that extracellular ATP can almost completely inhibit prestin motor activity in the outer hair cells. The effects of ATP on prestin are absent in mice lacking the TRPAI channels (Trpalj. Furthermore, direct activation of TRPA1 channels by specific agonists produces inhibition of prestin activity in Trpaf'~ but not in TrpaV' mice. Since TRPAI can participate in 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 Trpal"' mice as compared to Trpa1~'~ mice. The aim of this project is to determine how TRPAI channels participate in the protection of the cochlea from over-stimulation. This study will determine: 1) what specific intracochlear processes are affected by TRPAI deficiency; 2) the mechanism(s) of TRPAI activation in outer hair cells; and 3)the mechanism of TRPAI-mediated inhibition of the motor function of prestin. This study may open a new avenue of research in the field of noise-induced and perhaps other types of hearing loss.