ATP release through connexin hemichannels and gap junction transfer of second messengers propagate Ca
            <sup>2+</sup>
            signals across the inner ear

Anselmi, Fabio; Hernández, Victor H.; Crispino, Giulia; Seydel, Anke; Ortolano, Saida; Roper, Stephen D.; Kessaris, Nicoletta; Richardson, William D.; Rickheit, Gesa; Филиппов, М. А.; Monyer, Hannah; Mammano, Fabio

doi:10.1073/pnas.0800793105

Cited by 306 publications

(416 citation statements)

References 62 publications

(94 reference statements)

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“…This phenomenon could be blocked by extracellular apyrase-which hydrolyses ATP, and the PLC inhibitor U73122. The findings, including block of the Ca 2+ wave propagation using carbenoxolone, a gap junction blocker, suggested that the connexin hemichannel conduit for the ATP release in the cochlea [7,37] is coupled to P2Y receptor signaling [3]. Our data showing prominent P2Y2 receptor expression at this site is consistent with the initial immunolocalization of P2Y 2 to the Hensen's cell region by Gale et al [3].…”

Section: Discussionsupporting

confidence: 91%

“…ATP release has also been observed in the supporting cells in and adjacent to the organ of Corti [3][4][5] where the mechanism involves P2Y and P2X receptor signaling that could be induced by hair cell damage. Connexin and pannexin hemichannels are implicated in the ATP release mechanism [6][7][8]. The stria vascularis in the lateral wall of the cochlea is the source of the K + flux into scala media that establishes the driving force for sound transduction (the positive endocochlear potential).…”

Section: Introductionmentioning

confidence: 99%

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Differential expression of P2Y receptors in the rat cochlea during development

Huang

Thorne

Vlajkovic

et al. 2010

Purinergic Signalling

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Purinergic signaling has broad physiological significance to the hearing organ, involving signal transduction via ionotropic P2X receptors and metabotropic G-protein-coupled P2Y and P1 (adenosine), alongside conversion of nucleotides and nucleosides by ectonucleotidases and ecto-nucleoside diphosphokinase. In addition, ATP release is modulated by acoustic overstimulation or stress and involves feedback regulation. Many of these principal elements of the purinergic signaling complex have been well characterized in the cochlea, while the characterization of P2Y receptor expression is emerging. The present study used immunohistochemistry to evaluate the expression of five P2Y receptors, P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , and P2Y 12 , during development of the rat cochlea. Commencing in the late embryonic period, the P2Y receptors studied were found in the cells lining the cochlear partition, associated with establishment of the electrochemical environment which provides the driving force for sound transduction. In addition, early postnatal P2Y 2 and P2Y 4 protein expression in the greater epithelial ridge, part of the developing hearing organ, supports the view that initiation and regulation of spontaneous activity in the hair cells prior to hearing onset is mediated by purinergic signaling. Sub-cellular compartmentalization of P2Y receptor expression in sensory hair cells, and diversity of receptor expression in the spiral ganglion neurons and their satellite cells, indicates roles for P2Y receptormediated Ca 2+ -signaling in sound transduction and auditory neuron excitability. Overall, the dynamics of P2Y receptor expression during development of the cochlea complement the other elements of the purinergic signaling complex and reinforce the significance of extracellular nucleotide and nucleoside signaling to hearing.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Differential expression of P2Y receptors in the rat cochlea during development

Huang

Thorne

Vlajkovic

et al. 2010

Purinergic Signalling

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“…It has been found that cochlear ATP is mainly released from cochlear supporting cells via gap junction hemichannels [24]. In the local area near the cell surface, the ATP concentration would be high and can reach micromolar levels [24,28]. In this study, we found that the application of submicromolar and nanomolar ATP could evoke inward currents in the cochlear supporting cells (Fig.…”

Section: Discussionsupporting

confidence: 50%

ATP-mediated potassium recycling in the cochlear supporting cells

Zhu

Zhao

2010

Purinergic Signalling

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Gap junction-mediated K + recycling in the cochlear supporting cell has been proposed to play a critical role in hearing. However, how potassium ions enter into the supporting cells to recycle K + remains undetermined. In this paper, we report that ATP can mediate K + sinking to recycle K + in the cochlear supporting cells. We found that micromolar or submicromolar levels of ATP could evoke a K + -dependent inward current in the cochlear supporting cells. At negative membrane potentials and the resting membrane potential of −80 mV, the amplitude of the ATPevoked inward current demonstrated a linear relationship to the extracellular concentration of K + , increasing as the extracellular concentration of K + increased. The inward current also increased as the concentration of ATP was increased. In the absence of ATP, there was no evoked inward current for extracellular K + challenge in the cochlear supporting cells. The ATP-evoked inward current could be inhibited by ionotropic purinergic (P2X) receptor antagonists. Application of pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS, 50 µM) or pre-incubation with an irreversible P2X7 antagonist oxidized ATP (oATP, 0.1 mM) completely abolished the ATP-evoked inward current at the negative membrane potential. ATP also evoked an inward current at cell depolarization, which could be inhibited by intracellular Cs + and eliminated by positive holding potentials. Our data indicate that ATP can activate P2X receptors to recycle K + in the cochlear supporting cells at the resting membrane potential under normal physiological and pathological conditions. This ATP-mediated K + recycling may play an important role in the maintenance of cochlear ionic homeostasis.

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“…This close timing between the loss of tdTomato and the constriction by the SC suggests that SCs were likely responding to HC death, possibly signaled by the release of intracellular ATP. 4,40,41 It is also possible that HCs prime their surrounding SCs with a stress signal before they lose membrane integrity. The idea that HCs may signal their impending death is supported by our observation that dying HCs shrink for several hours before losing membrane integrity, a phenomenon that occurred in both neomycin-and cisplatintreated utricles.…”

Section: Discussionmentioning

confidence: 99%

Live imaging the phagocytic activity of inner ear supporting cells in response to hair cell death

et al. 2015

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Hearing loss and balance disorders affect millions of people worldwide. Sensory transduction in the inner ear requires both mechanosensory hair cells (HCs) and surrounding glia-like supporting cells (SCs). HCs are susceptible to death from aging, noise overexposure, and treatment with therapeutic drugs that have ototoxic side effects; these ototoxic drugs include the aminoglycoside antibiotics and the antineoplastic drug cisplatin. Although both classes of drugs are known to kill HCs, their effects on SCs are less well understood. Recent data indicate that SCs sense and respond to HC stress, and that their responses can influence HC death, survival, and phagocytosis. These responses to HC stress and death are critical to the health of the inner ear. Here we have used live confocal imaging of the adult mouse utricle, to examine the SC responses to HC death caused by aminoglycosides or cisplatin. Our data indicate that when HCs are killed by aminoglycosides, SCs efficiently remove HC corpses from the sensory epithelium in a process that includes constricting the apical portion of the HC after loss of membrane integrity. SCs then form a phagosome, which can completely engulf the remaining HC body, a phenomenon not previously reported in mammals. In contrast, cisplatin treatment results in accumulation of dead HCs in the sensory epithelium, accompanied by an increase in SC death. The surviving SCs constrict fewer HCs and display impaired phagocytosis. These data are supported by in vivo experiments, in which cochlear SCs show reduced capacity for scar formation in cisplatin-treated mice compared with those treated with aminoglycosides. Together, these data point to a broader defect in the ability of the cisplatin-treated SCs, to preserve tissue health in the mature mammalian inner ear. . 4 SCs perform many functions, including providing critical trophic factors, preventing excitotoxicity, and mediating regeneration in those systems (non-mammalian vertebrates) capable of replacing lost HCs. 5-11 When HCs die, SCs also preserve the integrity and function of the remaining tissue by forming scars and clearing dead HCs. 2,12-17 Maintaining a fluid barrier at the surface of the sensory epithelium after damage is necessary to preserve the electro-chemical gradient that drives HC depolarization and therefore sensory transduction after the onset of hearing (reviewed in Wangemann). 18 Several major stressors cause HC death, 19-22 including aging, noise trauma, and exposure to therapeutic drugs with ototoxic side effects. When a HC is killed by noise or aminoglycoside antibiotics, surrounding SCs form a filamentous actin (F-actin) cable that constricts the HC at its apex. 2,[12][13][14][15][16][17] This process separates the apical portion of the cell, including the stereocilia bundle, from the HC body and preserves a sealed reticular lamina. 23 In the chick utricle, following the apical constriction of dead HCs, the SCs engulf and phagocytose the remaining HC corpse. 15 Additional data from the chick indicate that the ototoxi...

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ATP release through connexin hemichannels and gap junction transfer of second messengers propagate Ca ²⁺ signals across the inner ear

Cited by 306 publications

References 62 publications

Differential expression of P2Y receptors in the rat cochlea during development

Differential expression of P2Y receptors in the rat cochlea during development

ATP-mediated potassium recycling in the cochlear supporting cells

Live imaging the phagocytic activity of inner ear supporting cells in response to hair cell death

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ATP release through connexin hemichannels and gap junction transfer of second messengers propagate Ca 2+ signals across the inner ear

Cited by 306 publications

References 62 publications

Differential expression of P2Y receptors in the rat cochlea during development

Differential expression of P2Y receptors in the rat cochlea during development

ATP-mediated potassium recycling in the cochlear supporting cells

Live imaging the phagocytic activity of inner ear supporting cells in response to hair cell death

Contact Info

Product

Resources

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ATP release through connexin hemichannels and gap junction transfer of second messengers propagate Ca ²⁺ signals across the inner ear