Upregulation of ATP-purinergic P2×2 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 P2×2 ATP-purinergic receptors in the cochlea links to hyperacusis generation. We found that P2×2 expression in the cochlea but not in auditory centers was upregulated in the hyperacusis generated by Cx26 deficiency. Overexpression of P2×2 in the cochlea also caused hyperacusis. Conversely, downregulation of P2×2 expression or administration of P2×2 antagonists attenuated hyperacusis. We further found that upregulation of P2×2 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 P2×2 receptor antagonists. Overall, these findings demonstrate that P2×2-mediated ATP-purinergic signaling in the cochlea plays a critical role in hyperacusis generation; targeting P2×2 receptors can attenuate hyperacusis stress, which may also offer a therapeutic strategy for other related psychological comorbidities.