Abstract
Extracellular adenosine 5'-triphosphate (ATP) is a key homeostatic regulator of sensory systems, with signal transduction via ATP-gated ion channels (P2X receptors) prominent across a broad range of mechanisms. This dependency of sense organs on ATP signaling is highlighted in the cochlea. Local autocrine/paracrine signaling by extracellular ATP within the cochlear partition is activated by sustained elevated noise and leads to protective desensitization of the outer hair cell-mediated “cochlear amplifier” and hence protects against glutamatergic excitotoxicity at the inner hair cell-type I spiral ganglion neuron synapses. Single-nucleotide polymorphisms of the P2RX2 gene encoding P2X2 receptor (P2X2) channels have been identified, which demonstrate the significance of this adaptive mechanism for sustained resistance to noise- and age-related hearing loss (DFNA41 autosomal dominant nonsyndromic hearing loss). The “purinergic hearing adaptation postulate” delineated here considers the purinergic interactome engaging P2X2 signaling, which likely drives a spectrum of vulnerability to hearing loss inherent to the diversity in the strength of the signaling process. This encompasses factors affecting how acoustic energy drives ATP release within the cochlear partition, the production and trafficking of P2X2 to the endolymph-facing membrane surfaces of the sensory hair cells, supporting cells, and epithelial tissues, as well as degradation processes (ecto-nucleotidases) and downstream signaling cascades associated with Ca2+ dynamics. All these “physiological elements” affected by gene expression, protein translation and posttranslational modifications, trafficking and chaperone proteins, in toto, confer unique individual profiles of otoprotection that likely in part contribute to the breadth of diversity in vulnerability to hearing loss in the population.