A PI3K Pathway Mediates Hair Cell Survival and Opposes Gentamicin Toxicity in Neonatal Rat Organ of Corti

Chung, Wingyan; Pak, Kwang; Lin, Bo; Webster, Nicholas J. G.; Ryan, Allen F.

doi:10.1007/s10162-006-0050-y

Cited by 55 publications

(78 citation statements)

References 62 publications

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“…Identification and characterization of the receptors and knowledge of peptide functions in cochlear development could enable us to design a peptide-based therapeutic strategy. Gentamicin exposure also activates pathways that promote HC survival in agreement with the current opinion that cells exist in a finely tuned balance between survival and cell death [58,59,60]. Some survival pathways that operate in HCs, such as the H-Ras/Raf/MEK/Erk pathway and the PI3K-Akt pathway, have been defined [61].…”

Section: Discussionmentioning

confidence: 49%

“…Some survival pathways that operate in HCs, such as the H-Ras/Raf/MEK/Erk pathway and the PI3K-Akt pathway, have been defined [61]. An interesting publication by Chung et al [58] demonstrated that PI3K/Akt mediates HC survival and opposes gentamicin toxicity in neonatal rat OC explants. We therefore asked whether the observed protection from gentamicin by SST might be due to the influence of SST on the PI3K/Akt pathway.…”

Section: Discussionmentioning

confidence: 99%

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Somatostatin Receptor Types 1 and 2 in the Developing Mammalian Cochlea

Bodmer

Brand²,

Radojević³

2012

Dev Neurosci

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The neuropeptide somatostatin (SST) exerts several important physiological actions in the adult central nervous system through interactions with membrane-bound receptors. Transient expression of SST and its receptors has been described in several brain areas during early ontogeny. It is therefore believed that SST may play a role in neural maturation. The present study provides the first evidence for the developmental expression of SST receptors in the mammalian cochlea, emphasizing their possible roles in cochlear maturation. In the developing mouse cochlea, cells immunoreactive to somatostatin receptor 1 (SSTR1) and somatostatin receptor 2 (SSTR2) were located in the embryonic cochlear duct on Kolliker’s organ as early as embryonic day (E) 14 (E14). At E17, the expression of both receptors was high and already located at the hair cells and supporting cells along the length of the cochlear duct, which have become arranged into the characteristic pattern for the organ of Corti (OC) at this stage. At birth, SSTR1- and SSTR2-containing cells were only localized in the OC. In general, immunoreactivity for both receptors increased in the mouse cochlea from postnatal day (P) 0 (P0) to P10; the majority of immunostained cells were inner hair cells, outer hair cells, and supporting cells. Finally, a peak in the mRNA and protein expression of both receptors is present near the time when they respond to physiological hearing (i.e., hearing of airborne sound) at P14. At P21, SSTR1 and SSTR2 levels decrease dramatically. A similar developmental pattern was observed for SSTR1 and SSTR2 mRNA, suggesting that the expression of the SSTR1 and SSTR2 genes is controlled at the transcriptional level throughout development. In addition, we observed reduced levels of phospho-Akt and total Akt in SSTR1 knockout and SSTR1/SSTR2 double-knockout mice compared with wild-type mice. We know from previous studies that Akt is involved in hair cell survival. Taken together, the dynamic nature of SSTR1 and SSTR2 expression at a time of major developmental changes in the cochlea suggests that SSTR1 and SSTR2 (and possibly other members of this family) are involved in the maturation of the mammalian cochlea.

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Section: Discussionmentioning

confidence: 49%

Section: Discussionmentioning

confidence: 99%

Somatostatin Receptor Types 1 and 2 in the Developing Mammalian Cochlea

Bodmer

Brand²,

Radojević³

2012

Dev Neurosci

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“…Moreover, KCNQ4 channels and I K,n (I K,L ) have been reported in type I vestibular HCs (3), but there are no reported balance abnormalities in subjects carrying KCNQ4 mutations (2) nor in the vestibular phenotype of mouse models of the disease (28). Because I K,n predominates and is a major contributor of outward currents in outer hair cells at the basal turn of the cochlea (8,27), basal HCs would be expected to undergo profound depolarization and gradual cell death ensuing from Ca 2ϩ -mediated cell death (29) if one variant of KCNQ4 is rendered nonfunctional by a DN mutation. In contrast, cochlear apical and vestibular HCs may not be severely affected since their membrane potentials are shaped by other K ϩ currents (27).…”

Section: Discussionmentioning

confidence: 99%

Roles of Alternative Splicing in the Functional Properties of Inner Ear-specific KCNQ4 Channels

Nie

Zhang

et al. 2007

Journal of Biological Chemistry

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The function of the KCNQ4 channel in the auditory setting is crucial to hearing, underpinned by the finding that mutations of the channel result in an autosomal dominant form of nonsyndromic progressive high frequency hearing loss. The precise function of KCNQ4 in the inner ear has not been established. However, recently we demonstrated that there is differential expression among four splice variants of KCNQ4 (KCNQ4_v1-v4) along the tonotopic axis of the cochlea. Alternative splicing specifies the outcome of functional channels by modifying the amino acid sequences within the C terminus at a site designated as the membrane proximal region. We show that variations within the C terminus of splice variants produce profound differences in the voltage-dependent phenotype and functional expression of the channel. KCNQ4_v4 lacks exons 9 -11, resulting in deletion of 54 amino acid residues adjacent to the S6 domain compared with KCNQ4_v1. Consequently, the voltagedependent activation of KCNQ4_v4 is shifted leftward by ϳ20 mV, and the number of functional channels is increased severalfold compared with KCNQ4_v1. The properties of KCNQ4_v2 and KCNQ4_v3 fall between KCNQ4_v1 and KCNQ4_v4. Because of variations in the calmodulin binding domains of the splice variants, the channels are differentially modulated by calmodulin. Co-expression of these splice variants yielded current magnitudes suggesting that the channels are composed of heterotetramers. Indeed, a dominant negative mutant of KCNQ4_v1 cripples the currents of the entire KCNQ4 channel family. Furthermore, the dominant negative KCNQ4 mutant stifles the activity of KCNQ2-5, raising the possibility of a global disruption of KCNQ channel activity and the ensuing auditory phenotype.KCNQ channels constitute delayed-rectifier K ϩ channels found in a wide range of excitable and non-excitable cells to control their membrane potentials and in so doing regulate Ca 2ϩ influx. In the inner ear KCNQ channels are critical for auditory function, as mutations of KCNQ1 and KCNQ4 result in deafness and PHFHL, 4 respectively (1-4). Within the cochlea, four members of the KCNQ channel family have been identified by RT-PCR technique (2); however, only the expression of KCNQ1 and KCNQ4 has been demonstrated and studied in detail (2, 3, 5). The expression of KCNQ1 is restricted mainly to marginal cells of the stria vascularis, and mutations of the channel abolish the endocochlear potential (5-7). In contrast, KCNQ4 has been identified chiefly in outer and inner hair cells and spiral ganglion neurons (4, 8 -10). We have previously shown that there is differential expression among the four splice variants of KCNQ4 (KCNQ4_v1-4) along the tonotopic axis of the cochlea (8). The location-dependent variability in KCNQ4 expression suggests that KCNQ4 channels in the cochlear duct serve specialized physiological functions.A straightforward but accurate model of KCNQ and other K ϩ channel physiology in the inner ear maintains that the channels serve to regulate membrane potential to modulate the l...

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“…Phosphatidylinositide 3'-OK kinase (PI3K) is recently reported to resist gentamycin ototoxicity in postnatal rat organ of Corti [9], suggestive of involvement in the hair cell survival in vivo. BDNF receptor is a tyrosine kinase (TrkB) that activates the PI3K which in turn recruits protein kinase B (Akt) to the plasma membrane [10,11].…”

Section: Introductionmentioning

confidence: 99%

BDNF Promotes the Survival of Rat Sensory Epithelial Cells Via the PI3K/Akt and NF-􀀂B/Bcl-2 Signaling Pathways

Huang

Ling

et al. 2013

TONEURJ

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Sensory epithelial cells in the organ of Corti survive throughout life. However, factors for sensory epithelial cell survival are poorly understood at the present time. Here we demonstrated that brain-derived neurotrophic factor (BDNF), a factor committing to neuronal survival, promotes the survival of sensory epithelial cells (OC1) through phosphatidylinositide 3'-OH kinase (PI3K)/protein kinase B (Akt) and/or nuclear factor kappa B (NF-B)/B cell lymphoma 2 (Bcl-2) pathways. BDNF activated PI3K/Akt kinases and increased NF-B/Bcl-2 activity or expression in association with the survival of OC1 cells in vitro. LY294002, a specific inhibitor for PI3K, and pyrrolidine dithiocarbamate (PDTC), an inhibitor for NF-B, abrogated the protective effect of BDNF on OC1 cells, causing the increased expression of caspase 3 and the apoptotic cell numbers in vitro. Similarly, a dominant negative mutant of I kappa B alpha (I B M, a specific inhibitor of NF-B) abrogated the protective effect of BDNF on OC1 cells. The data demonstrate that BDNF promotes the survival of sensory epithelial cells through the PI3K/Akt and NF-B/Bcl-2 signaling pathways.

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A PI3K Pathway Mediates Hair Cell Survival and Opposes Gentamicin Toxicity in Neonatal Rat Organ of Corti

Cited by 55 publications

References 62 publications

Somatostatin Receptor Types 1 and 2 in the Developing Mammalian Cochlea

Somatostatin Receptor Types 1 and 2 in the Developing Mammalian Cochlea

Roles of Alternative Splicing in the Functional Properties of Inner Ear-specific KCNQ4 Channels

BDNF Promotes the Survival of Rat Sensory Epithelial Cells Via the PI3K/Akt and NF-􀀂B/Bcl-2 Signaling Pathways

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