Abstract
Pannexin1 (Panx1) is a gap junction gene in vertebrates whose proteins mainly function as non-junctional channels on the cell surface. Panx1 channels can release ATP under physiological conditions and play critical roles in many physiological and pathological processes. Here, we report that Panx1 deficiency can reduce ATP release and endocochlear potential (EP) generation in the cochlea inducing hearing loss. Panx1 extensively expresses in the cochlea, including the cochlear lateral wall. We found that deletion of Panx1 in the cochlear lateral wall almost abolished ATP release under physiological conditions. Positive EP is a driving force for current through hair cells to produce auditory receptor potential. EP generation requires ATP. In the Panx1 deficient mice, EP and auditory receptor potential as measured by cochlear microphonics (CM) were significantly reduced. However, no apparent hair cell loss was detected. Moreover, defect of connexin hemichannels by deletion of connexin26 (Cx26) and Cx30, which are predominant connexin isoforms in the cochlea, did not reduce ATP release under physiological conditions. These data demonstrate that Panx1 channels dominate ATP release in the cochlea ensuring EP and auditory receptor potential generation and hearing. Panx1 deficiency can reduce ATP release and EP generation causing hearing loss.
Highlights
Pannexins and connexins belong to gap junction gene families in vertebrates
We found that ATP can mediate outer hair cell (OHC) electromotility to regulate hearing sensitivity, gap junctional coupling between the cochlear supporting cells, and K+-recycling[29,30,31,32]
Positive endocochlear potential (EP) is generated in the cochlear lateral wall[33,36] and is a driving force that compels K+ ions in the endolymph through the transduction channels at stereocilia of hair cells to produce auditory receptor current and potential, thereby initiating hearing
Summary
Pannexins and connexins belong to gap junction gene families in vertebrates. they have completely different sequences[1,2]. Panx[1] channels can be activated by mechanical stress, low oxygen, glutamate through NMDA receptors, elevation of extracellular K+ concentrations, and ATP binding to purinergic receptors[3,8,9,10,11,12,13] These specific properties imply that pannexin channels can function in a wider range of physiological conditions. Panx[2] only expresses at the basal cell layer in the stria vascularis, and Panx[3] expression is restricted to the cochlear bone These distinct distribution patterns suggest that pannexins play important roles in the inner ear. We found that deletion of Panx[1] in the cochlear lateral wall reduced ATP release and EP generation and thereby reduced auditory receptor potential leading to hearing loss. This indicates that Panx[1] is required for EP generation and hearing
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