Role of TRPA1 channel in noise and drug induced hearing loss

RESEARCH PROJECT MATERIALS I. ABSTRACT Principal Investigator: Stepanyan, Ruben Approximately 10 percent of Americans, including one third of people over the age of 60, have some degree of hearing loss. Roughly, one third of all the hearing impaired can attribute their hearing loss to noise. In fact, more than 30 million Americans are regularly exposed to hazardous noise. In addition, a common cause of hearing loss, especially in developing countries, is ototoxicity. An ototoxic hearing loss happens when someone takes or is given a drug that causes loss of hearing as one of its side effects. It is likely that in some cases exposure to hazardous noise will take place during treatment with drug that might cause ototoxic hearing loss. However, it is not known if there is any interaction between two causes of hearing loss. Hearing sensitivity in mammals is enhanced more than 1DO-fold by mechanical amplification of cochlear sensory cells, the outer hair cells. Damage to outer hair cells results in distinct and dramatic hearing loss. Attenuating cochlear amplification is proposed to be an important mechanism for outer hair cells' protection during exposures to high-level noise. One of the known phenomenon during exposure to high-level noise is increased level of adenosine triphosphate (ATP) in both cochlear endolymph and perilymph. Cochlear mechanosensory outer hair cells response to extracellular ATP via ionotropic P2X and metabotropic P2Y receptors. These responses are believed to mediate protection of the cochlea against overstimulation by high-level noise; however the mechanism is still unknown. Our preliminary data show that activation of outer hair cells TRPA 1 channel results in inhibition of prestin-driven electromotility, which attenuates hearing sensitivity as a protection from overstimulation by high-level noise. Considering that outer hair cells express both metabotropic G-protein coupled ATP receptor, P2Y, and TRPA 1 ion channel then we can suggest that through this P2Y receptor ATP activates the outer hair cell TRPA 1 ion channels "classically", as a downstream target. Ototoxic drugs such as gentamicyn and kanamicyn enter the hair cell through mechanotransduction channels which represent nonselective cation channels. Pharmacological properties of TRPA 1 channel are very close and therefore we expect that TRPA 1 will provide additional pathway for the entry of these drugs into the hair cells. Based on our preliminary data, we suggest that noise exposure will increase ATP level in cochlea, which will activate P2Y - TRPA 1 transduction pathway. Ototoxic drug will enter the outer hair cells through open TRPA 1 channels and exaggerate noise induced hearing loss. Here we propose 1) to test the hypothesis that TRPA 1 channel in outer hair cells is permeable to small cation molecules and ototoxic antibiotics 2) to test the hypothesis that noise exposure enhances susceptibility to drug induced hearing loss in mice. The significance and impact of hearing loss on health and productivity are often underestimated. Untreated hearing loss has an enormous impact on the overall health of individuals - it can lead to social isolation, confusion, frustration, tension, stress, and depression. By understanding the mechanisms of ototoxic insult, our efforts will contribute to the ultimate goal of developing strategies to ameliorate drug induced hearing loss. Page 1