A Mechanism for Sensing Noise Damage in the Inner Ear

Gale, Jonathan E.; Piazza, Valeria; Ciubotaru, Catalin D.; Mammano, Fabio

doi:10.1016/j.cub.2004.03.002

Cited by 130 publications

(185 citation statements)

References 16 publications

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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: 90%

“…With the exception of P2Y 12 , expression of all these receptors has previously been confirmed in rat cochlear tissues by RT-PCR [3,26]. We complemented this in the present study by confirming P2Y12 transcript expression by RT-PCR alongside immunolocalisation of the five P2Y proteins.…”

Section: Rt-pcr Detection Of P2y12 Receptor Mrna Transcriptsupporting

confidence: 83%

“…This has been identified in the neonatal rat organ of Corti [3,4]. Either exogenously applied nanomolar concentrations of ATP or UTP, or focal ATP release via laser ablation of sensory hair cells initiated Ca 2+ waves through the lateral supporting cells (Hensen cells; via the P2Y-PLC-IP 3 pathway).…”

Section: Discussionmentioning

confidence: 99%

“…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]. That study demonstrated that members of the mitogen-activated protein kinases (MAPK) pathway were correlated with expression of the P2Y 2 receptors and an ATP-dependent Ca 2+ wave, as part of an injury response mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…Both P2X receptors (ATP-gated ion channels and P2Y (G-protein-coupled) receptors are implicated. 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].…”

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: 90%

Section: Rt-pcr Detection Of P2y12 Receptor Mrna Transcriptsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Differential expression of P2Y receptors in the rat cochlea during development

Huang

Thorne

Vlajkovic

et al. 2010

Purinergic Signalling

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Gap Junctions and Connexins: The Molecular Genetics of Deafness

Nickel

Forge

2010

Encyclopedia of Life Sciences

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Mutations in the gene GJB2 encoding the gap‐junction protein connexin 26 ( Cx26 ), in particular, and in GJB6 coding for connexin 30 ( Cx30 ) are the most common cause of autosomal recessive sensorineural hearing loss in many world populations. Variants of GJB2 are also associated with dominant forms of both nonsyndromic and syndromic deafness. A complex picture of the roles of gap junctions in cochlear physiology has emerged. Rather than being mere conduits for the circulation of potassium ions in the inner ear, gap junctions have been implicated in the maintenance of metabolic homeostasis and in intercellular signalling among nonsensory cells. Studies of mutant channels and mouse models for connexin ‐related deafness have provided valuable insights into the heterogeneous mechanisms by which connexin mutations may cause cochlear dysfunction. Despite recent advances it is still not fully understood what roles gap junctions play in the inner ear and how connexin mutations cause deafness. Key Concepts: GJB2 and GJB6 have been mapped to the DFNB1 locus, which accounts for up to 50% of all cases of autosomal recessive nonsyndromic hearing loss. Molecular genetic tests for DFNB1 should include DNA sequencing of the GJB2 exons and mutation analysis for GJB6 deletions. The identification of factors underlying the phenotypic variability of connexin‐related hearing loss may improve clinical diagnosis and genetic counselling. A better understanding of the role of gap‐junctional communication in the inner ear and the structure–function relationships of connexin proteins is required for the development of mechanism‐based treatments of connexin‐associated hearing loss.

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Ca2+ homeostasis defects and hereditary hearing loss

Mammano

2011

BioFactors

Self Cite

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Ca(2+) acts as a fundamental signal transduction element in inner ear, delivering information about sound, acceleration and gravity through a small number of mechanotransduction channels in the hair cell stereocilia and voltage activated Ca(2+) channels at the ribbon synapse, where it drives neurotransmission. The mechanotransduction process relies on the endocochlear potential, an electrical potential difference between endolymph and perilymph, the two fluids bathing respectively the apical and basolateral membrane of the cells in the organ of Corti. In mouse models, deafness and lack or reduction of the endocochlear potential correlate with ablation of connexin (Cx) 26 or 30. These Cxs form heteromeric channels assembled in a network of gap junction plaques connecting the supporting and epithelial cells of the organ of Corti presumably for K(+) recycle and transfer of key metabolites, for example, the Ca(2+) -mobilizing second messenger IP(3) . Ca(2+) signaling in these cells could play a crucial role in regulating Cx expression and function. Another district where Ca(2+) signaling alterations link to hearing loss is hair cell apex, where ablation or missense mutations of the PMCA2 Ca(2+) -pump of the stereocilia cause deafness and loss of balance. If less Ca(2+) is exported from the stereocilia, as in the PMCA2 mouse mutants, Ca(2+) concentration in endolymph is expected to fall causing an alteration of the mechanotransduction process. This may provide a clue as to why, in some cases, PMCA2 mutations potentiated the deafness phenotype induced by coexisting mutations of cadherin-23 (Usher syndrome type 1D), a single pass membrane Ca(2+) binding protein that is abundantly expressed in the stereocilia.

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A Mechanism for Sensing Noise Damage in the Inner Ear

Cited by 130 publications

References 16 publications

Differential expression of P2Y receptors in the rat cochlea during development

Differential expression of P2Y receptors in the rat cochlea during development

Gap Junctions and Connexins: The Molecular Genetics of Deafness

Ca2+ homeostasis defects and hereditary hearing loss

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