Purinergic signaling in the organ of Corti: Potential therapeutic targets of sensorineural hearing losses

Berekméri, Eszter; Szepesy, Judit; Köles, László; Zelles, Tibor

doi:10.1016/j.brainresbull.2019.01.029

Cited by 14 publications

(23 citation statements)

References 137 publications

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“…In Köllicker's organ and the organ of Corti, ATP activates purinergic receptors in surrounding SCs, inner HCs, and dendrites of primary auditory neurons ( Glowatzki et al., 1997 ; Housley et al., 1998 , 1999 ; Järlebark et al., 2000 , 2002 ; Parker et al., 1998 ; Salih et al., 1999 ; Sueta et al., 2003 ; Szücs et al., 2004 ; Telang et al., 2010 ; Wang et al., 2003 ; Yan and Gu, 2013 ; Zhao et al., 2005 ; Chen et al., 1998 ). ATP can increase membrane conductance, cause rises in Ca 2+ , and significantly change SC morphologies during development ( Berekméri et al., 2019 ). Therefore, we tested the effects of ATP on possible purinergic signaling during development in clinocytes and clino2 cells.…”

Section: Resultsmentioning

confidence: 99%

Developmental GAD2 Expression Reveals Progenitor-like Cells with Calcium Waves in Mammalian Crista Ampullaris

2020

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Summary Sense of motion, spatial orientation, and balance in vertebrates relies on sensory hair cells in the inner ear vestibular system. Vestibular supporting cells can regenerate hair cells that are lost from aging, ototoxicity, and trauma, although not all factors or specific cell types are known. Here we report a population of GAD2-positive cells in the mouse crista ampullaris and trace GAD2 progenitor-like cells that express pluripotent transcription factors SOX2, PROX1, and CTBP2. GAD2 progenitor-like cells organize into rosettes around a central branched structure in the eminentia cruciatum (EC) herein named the EC plexus. GCaMP5G calcium indicator shows spontaneous and acetylcholine-evoked whole-cell calcium waves in neonatal and adult mice. We present a hypothetical model that outlines the lineage and potential regenerative capacity of GAD2 cells in the mammalian vestibular neuroepithelium.

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Section: Resultsmentioning

confidence: 99%

Developmental GAD2 Expression Reveals Progenitor-like Cells with Calcium Waves in Mammalian Crista Ampullaris

2020

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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).…”

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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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“…To create ATP-WCBs, we infected HEK-293T cells with a lentiviral vector encoding the highly sensitive P2Y 2 R, one of the two major P2Y receptors expressed in the developing cochlea. 3,6 The binding of ATP to P2Y 2 R promotes the generation of diacylglycerol and InsP 3 from PLC-dependent hydrolysis of PIP 2 . 18 Intracellular diffusion of InsP 3 and subsequent binding to InsP 3 receptors triggers Ca 2+ release from the endoplasmic reticulum (ER), increasing the cytosolic Ca 2+ concentration.…”

Section: Discussionmentioning

confidence: 99%

“…Extracellular ATP modulates the function of both sensory and non-sensory cells in the inner ear (reviewed in ref. [1][2][3]. In the developing cochlea, ATP triggers cytosolic Ca 2+ concentration oscillations and propagation of intercellular Ca 2+ waves that carry crucial biochemical information to the cochlear sensory epithelium.…”

Section: Introductionmentioning

confidence: 99%

Organ-on-chip model shows that ATP release through connexin hemichannels drives spontaneous Ca²⁺ signaling in non-sensory cells of the greater epithelial ridge in the developing cochlea

et al. 2020

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Purinergic signaling in the organ of Corti: Potential therapeutic targets of sensorineural hearing losses

Cited by 14 publications

References 137 publications

Developmental GAD2 Expression Reveals Progenitor-like Cells with Calcium Waves in Mammalian Crista Ampullaris

Developmental GAD2 Expression Reveals Progenitor-like Cells with Calcium Waves in Mammalian Crista Ampullaris

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

Organ-on-chip model shows that ATP release through connexin hemichannels drives spontaneous Ca²⁺ signaling in non-sensory cells of the greater epithelial ridge in the developing cochlea

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Purinergic signaling in the organ of Corti: Potential therapeutic targets of sensorineural hearing losses

Cited by 14 publications

References 137 publications

Developmental GAD2 Expression Reveals Progenitor-like Cells with Calcium Waves in Mammalian Crista Ampullaris

Developmental GAD2 Expression Reveals Progenitor-like Cells with Calcium Waves in Mammalian Crista Ampullaris

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

Organ-on-chip model shows that ATP release through connexin hemichannels drives spontaneous Ca2+ signaling in non-sensory cells of the greater epithelial ridge in the developing cochlea

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Organ-on-chip model shows that ATP release through connexin hemichannels drives spontaneous Ca²⁺ signaling in non-sensory cells of the greater epithelial ridge in the developing cochlea