The sense of hearing is remarkable for its auditory dynamic range, which spans more than 10 12 in acoustic intensity. The mechanisms that enable the cochlea to transduce high sound levels without damage are of key interest, particularly with regard to the broad impact of industrial, military, and recreational auditory overstimulation on hearing disability. We show that ATP-gated ion channels assembled from P2X 2 receptor subunits in the cochlea are necessary for the development of temporary threshold shift (TTS), evident in auditory brainstem response recordings as sound levels rise. In mice null for the P2RX2 gene (encoding the P2X 2 receptor subunit), sustained 85-dB noise failed to elicit the TTS that wild-type (WT) mice developed. ATP released from the tissues of the cochlear partition with elevation of sound levels likely activates the broadly distributed P2X 2 receptors on epithelial cells lining the endolymphatic compartment. This purinergic signaling is supported by significantly greater noise-induced suppression of distortion product otoacoustic emissions derived from outer hair cell transduction and decreased suprathreshold auditory brainstem response input/output gain in WT mice compared with P2RX2-null mice. At higher sound levels (≥95 dB), additional processes dominated TTS, and P2RX2-null mice were more vulnerable than WT mice to permanent hearing loss due to hair cell synapse disruption. P2RX2-null mice lacked ATP-gated conductance across the cochlear partition, including loss of ATP-gated inward current in hair cells. These data indicate that a significant component of TTS represents P2X 2 receptordependent purinergic hearing adaptation that underpins the upper physiological range of hearing.noise-induced hearing loss | acoustic overstimulation | permanent threshold shift | auditory neurotransmission | sound transduction S ensory systems are characterized by adaptation processes that sustain transduction as stimulus intensity increases. The mammalian auditory system operates across an acoustic power range of 120 dB, measured on the logarithmic decibel scale. The mechanism for the extraordinary acuity of the cochlea (recalling the ageold adage of "hearing a pin drop") arises from the commitment of 75% of the sensory hair cells, the outer hair cells, to electromechanical (reverse) transduction, driving a "cochlear amplifier." The nonlinear outer hair cell reverse transduction provides an ∼40-dB gain at hearing threshold, reducing to zero as sound levels rise (1). A major challenge for auditory physiology is to understand how hearing is preserved in the face of acoustic overstimulation, as noise can damage the cochlea and can greatly exacerbate hearing loss with aging (2). Given the recent propensity for direct delivery of high-level recreational sound to the ear canals by personal music players and, more broadly, the impact on our hearing of noise from industrial and military environments, there is an imperative to better understand the intrinsic mechanisms that enable the cochlea to accommodate lo...

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In the cochlea, Reissner's membrane separates the scala media endolymphatic compartment that sustains the positive endocochlear potential and ion composition necessary for sound transduction, from the scala vestibuli perilymphatic compartment. It is known that with sustained elevated sound levels, adenosine 5 -triphosphate (ATP) is released into the endolymph and ATP-gated ion channels on the epithelial cells lining the endolymphatic compartment shunt the electrochemical driving force, contributing to protective purinergic hearing adaptation. This study characterises the properties of epithelial cell P2X 2 -type ATP-activated membrane conductance in the mouse Reissner's membrane, which forms a substantial fraction of the scale media surface. The cells were found to express two isoforms (a and b) of the P2X 2 subunit arising from alternative splicing of the messenger RNA (mRNA) transcript that could contribute to the trimeric subunit assembly. The ATP-activated conductance demonstrated both immediate and delayed desensitisation consistent with incorporation of the combination of P2X 2 subunit isoforms. Activation by the ATP analogue 2meSATP had equipotency to ATP, whereas α,β-meATP and adenosine 5′-diphosphate (ADP) were ineffective. Positive allosteric modulation of the P2X 2 channels by protons was profound. This native conductance was blocked by the P2X 2 -selective blocker pyridoxalphosphate-6-azophenyl-2 ,4 -disulphonic acid (PPADS) and the conductance was absent in these cells isolated from mice null for the P2rX2 gene encoding the P2X 2 receptor subunit. The activation and desensitisation properties of the Reissner's membrane epithelial cell ATP-gated P2X 2 channels likely contribute to the sensitivity and kinetics of purinergic control of the electrochemical driving force for sound transduction invoked by noise exposure.