Upregulation of ATP-purinergic P2x2 receptors in the cochlea over-amplifies hearing sensitivity leading to hyperacusis and attenuation by antagonists

Hearing hypersensitivity (hyperacusis) is a common hearing stress and can cause many psychological diseases, e.g., anxiety, learning disabilities, and attention-deficit/hyperactivity disorder (ADHD). Here, we report an unexpected finding that the upregulation of P2x2 ATP-purinergic receptors in the cochlea links to hyperacusis generation. We found that P2x2 expression in the cochlea but not in auditory centers was upregulated in the hyperacusis generated by Cx26 deficiency. Overexpression of P2x2 in the cochlea also caused hyperacusis. Conversely, downregulation of P2x2 expression or administration of P2x2 antagonists attenuated hyperacusis. We further found that upregulation of P2x2 receptors in the cochlea increased outer hair cell (OHC) electromotility through the post-transcription functional modulation to potentiate active cochlear amplification leading to hearing hypersensitivity. Such enhancements in OHC electromotility and active cochlear amplification were also suppressed by P2x2 receptor antagonists. Overall, these findings demonstrate that P2x2-mediated ATP-purinergic signaling in the cochlea plays a critical role in hyperacusis generation; targeting P2x2 receptors can attenuate hyperacusis stress, which may also offer a therapeutic strategy for other related psychological comorbidities. Significance statementHearing hypersensitivity is a common hearing stress and can cause many other psychological disorders. However, little is known about the underlying genetic and cellular mechanisms. Also, it lacks efficient drugs for their treatments in the clinic. In this study, we found that upregulation of P2x2 ATP-purinergic receptors in the cochlea can potentiate outer hair cell electromotility, which is an active cochlear amplifier in mammals and can increase hearing sensitivity and frequency selectivity, through post-transcription functional modulation to enhance active cochlear amplification leading to hearing hypersensitivity. These enhancements can be inhibited by administrations of P2x2 receptor antagonists both in vitro and in vivo. These findings revealed a new genetic and cellular mechanism underlying hyperacusis generation and opened a new avenue to develop an efficient therapy for this common hearing stress and other associated psychological comorbidities.