Properties of ATP-gated ion channels assembled from P2X2 subunits in mouse cochlear Reissner’s membrane epithelial cells

Morton-Jones, Rachel T.; Vlajkovic, Srdjan M.; Thorne, Peter R.; Cockayne, Debra A.; Ryan, Allen F.; Housley, Gary D.

doi:10.1007/s11302-015-9473-4

Cited by 18 publications

(11 citation statements)

References 39 publications

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“…Purinergic signaling is sensitive to pathophysiological changes (e.g., due to noise or ischemia) of the extracellular milieu and thereby can promptly react and initiate protective mechanisms. This control function of the purinergic system has been delineated in sound sensitivity of the cochlea and in NIHLs [74,166]. Noise trauma induces various events and purinergic mechanisms are involved in this machinery.…”

Section: Purinergic Signaling and Sensorineural Hearing Lossesmentioning

confidence: 99%

Purinergic Signaling and Cochlear Injury-Targeting the Immune System?

Köles

Szepesy

Berekméri

et al. 2019

IJMS

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Hearing impairment is the most common sensory deficit, affecting more than 400 million people worldwide. Sensorineural hearing losses currently lack any specific or efficient pharmacotherapy largely due to the insufficient knowledge of the pathomechanism. Purinergic signaling plays a substantial role in cochlear (patho)physiology. P2 (ionotropic P2X and the metabotropic P2Y) as well as adenosine receptors expressed on cochlear sensory and non-sensory cells are involved mostly in protective mechanisms of the cochlea. They are implicated in the sensitivity adjustment of the receptor cells by a K+ shunt and can attenuate the cochlear amplification by modifying cochlear micromechanics. Cochlear blood flow is also regulated by purines. Here, we propose to comprehend this field with the purine-immune interactions in the cochlea. The role of harmful immune mechanisms in sensorineural hearing losses has been emerging in the horizon of cochlear pathologies. In addition to decreasing hearing sensitivity and increasing cochlear blood supply, influencing the immune system can be the additional avenue for pharmacological targeting of purinergic signaling in the cochlea. Elucidating this complexity of purinergic effects on cochlear functions is necessary and it can result in development of new therapeutic approaches in hearing disabilities, especially in the noise-induced ones.

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Section: Purinergic Signaling and Sensorineural Hearing Lossesmentioning

confidence: 99%

Purinergic Signaling and Cochlear Injury-Targeting the Immune System?

Köles

Szepesy

Berekméri

et al. 2019

IJMS

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“…The P2X2 receptor is expressed in the cochlea where it is thought to localize to hair cells, as well as Reisner's membrane epithelial cells that maintain the integrity of the endolymphatic compartment (3,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). ATP released into the endolymphatic compartment in response to loud noise has been proposed to activate P2X2 receptors in the Reisner's membrane and to thereby produce a cation shunt that reduces the endolymphatic potential and the driving force for sound transduction (11).…”

mentioning

confidence: 99%

Hearing loss mutations alter the functional properties of human P2X2 receptor channels through distinct mechanisms

George

Swartz

2019

Proc. Natl. Acad. Sci. U.S.A.

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Activation of P2X2 receptor channels by extracellular ATP is thought to play important roles in cochlear adaptation to elevated sound levels and protection from overstimulation. Each subunit of a trimeric P2X2 receptor is composed of intracellular N and C termini, a large extracellular domain containing the ATP binding site and 2 transmembrane helices (TM1 and TM2) that form a cation permeable pore. Whole-exome sequencing and linkage analysis have identified 3 hP2X2 receptor mutations (V60L, D273Y, and G353R) that cause dominantly inherited progressive sensorineural hearing loss (DFNA41). Available structures of related P2X receptors suggest that these 3 mutations localize to TM1 (V60L), TM2 (G353R), or the β-sheet linking the TMs to the extracellular ATP binding sites (D273Y). Previous studies have concluded that the V60L and G353R mutants are nonfunctional, whereas the D273Y mutant has yet to be studied. Here, we demonstrate that both V60L and G353R mutations do form functional channels, whereas the D273Y mutation prevents the expression of functional channels on the cell membrane. Our results show that the V60L mutant forms constitutively active channels that are insensitive to ATP or the antagonist suramin, suggesting uncoupling of the pore and the ligand binding domains. In contrast, the G353R mutant can be activated by ATP but exhibits alterations in sensitivity to ATP, inward rectification, and ion selectivity. Collectively, our results demonstrate that the loss of functional P2X2 receptors or distinct alterations of its functional properties lead to noise-induced hearing loss, highlighting the importance of these channels in preserving hearing.

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“…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 (Housley et al, ; Yan et al, ; Mittal et al, ,c). A study aimed at characterizing the properties of these epithelial cells (Morton‐Jones et al, ). It was concluded that the activation and desensitization properties of the Reissner's membrane epithelial cell ATP‐gated P2 × 2 channel likely contribute to the sensitivity and kinetics of purinergic control of the electrochemical driving force for sound transduction invoked by noise exposure.…”

Section: Complexity Of the Auditory Systemmentioning

confidence: 99%

Signaling in the Auditory System: Implications in Hair Cell Regeneration and Hearing Function

Mittal

Debs

Nguyen

et al. 2017

Journal Cellular Physiology

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Ear is a sensitive organ involved in hearing and balance function. The complex signaling network in the auditory system plays a crucial role in maintaining normal physiological function of the ear. The inner ear comprises a variety of host signaling pathways working in synergy to deliver clear sensory messages. Any disruption, as minor as it can be, has the potential to affect this finely tuned system with temporary or permanent sequelae including vestibular deficits and hearing loss. Mutations linked to auditory symptoms, whether inherited or acquired, are being actively researched for ways to reverse, silence, or suppress them. In this article, we discuss recent advancements in understanding the pathways involved in auditory system signaling, from hair cell development through transmission to cortical centers. Our review discusses Notch and Wnt signaling, cell to cell communication through connexin and pannexin channels, and the detrimental effects of reactive oxygen species on the auditory system. There has been an increased interest in the auditory community to explore the signaling system in the ear for hair cell regeneration. Understanding signaling pathways in the auditory system will pave the way for the novel avenues to regenerate sensory hair cells and restore hearing function. J. Cell. Physiol. 232: 2710-2721, 2017. © 2016 Wiley Periodicals, Inc.

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Properties of ATP-gated ion channels assembled from P2X2 subunits in mouse cochlear Reissner’s membrane epithelial cells

Cited by 18 publications

References 39 publications

Purinergic Signaling and Cochlear Injury-Targeting the Immune System?

Purinergic Signaling and Cochlear Injury-Targeting the Immune System?

Hearing loss mutations alter the functional properties of human P2X2 receptor channels through distinct mechanisms

Signaling in the Auditory System: Implications in Hair Cell Regeneration and Hearing Function

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