Connexins 26 and 30 are co-assembled to form gap junctions in the cochlea of mice

Ahmad, Shoab; Chen, Shanping; Sun, Jianjun; Lin, Xiaobo

doi:10.1016/s0006-291x(03)01166-5

Cited by 181 publications

(210 citation statements)

References 26 publications

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“…Similar findings have been reported for both connexin 26 and connexin 30 (Ahmad et al 2003;Forge et al 2003). Sparse staining for connexin 26 for cells in this region was also noted in the initial report on its localization in rat (Kikuchi et al 1995).…”

Section: Cytochemistry Of Type IV Fibrocytessupporting

confidence: 85%

Immunocytochemical Traits of Type IV Fibrocytes and Their Possible Relations to Cochlear Function and Pathology

Adams

2009

JARO

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One of the more consistent and least understood changes in the aging human cochlea is the progressive loss of fibrocytes within the spiral ligament. This report presents an animal model for type IV fibrocyte loss, along with immunocytochemical evidence that noise-induced loss of these cells may account for previously unexplained hearing losses. The remarkably low threshold for noise-induced loss of type IV fibrocytes, approximately 24 dB less than the threshold for adjacent hair cell destruction, may account for the prevalence of missing fibrocytes in humans. In mice, changes in the spectrum of traumatizing noise had little effect upon the site of loss of the fibrocytes, suggesting that the primary site of damage that induced the loss was the basal-most cochlear turn, a site expected to be damaged by all three noise bands. Type IV fibrocytes were found to immunostain for connective tissue growth factor (CTGF) and for transforming growth factor beta receptor 3, a receptor that is known to activate CTGF expression. Type IV fibrocytes lack immunostaining for adenosine triphosphatase and connexins that are key players in potassium ion uptake and transmission, which suggests that they play little, if any, role in potassium recycling from perilymphatic space to the endolymphatic space. Consequently, their loss probably does not directly reduce this process. Immunostaining for a receptor for CTGF, low-density-lipoprotein-related protein 1, indicated that CTGF acts as an autocrine and a paracrine agent within the cochlea. The lack of CTGF paracrine effects following noise-induced loss of type IV fibrocytes may account for previously unexplained hearing losses.

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Section: Cytochemistry Of Type IV Fibrocytessupporting

confidence: 85%

Immunocytochemical Traits of Type IV Fibrocytes and Their Possible Relations to Cochlear Function and Pathology

Adams

2009

JARO

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“…The direct introduction of Ca 2ϩ into cells by adding up to 20 mM CaCl 2 in the pipette internal solution failed to initiate the propagation of Ca 2ϩ waves, which showed that IP 3 -initiated Ca 2ϩ waves were not due to intercellular Ca 2ϩ diffusion. To further determine the involvement of GJs in Ca 2ϩ wave propagation, we tested whether IP 3 injection induced Ca 2ϩ waves in supporting cells of P1 cochlea. Consistent with the absence of Cx immunoreactivity in supporting cells at this time point (Fig.…”

Section: Gjs In Supporting Cells Mediated the Propagation Of Ca 2؉ Wamentioning

confidence: 99%

“…Cx26 and Cx30 are the two major types of Cxs found in the cochlear supporting cells and fibrocytes (1)(2)(3)(4). Genetic linkage studies demonstrate that Cx mutations are found in approximately half of deaf patients with nonsyndromic sensorineural hearing loss (5,6).…”

mentioning

confidence: 99%

“…We have used two-electrode patch-clamp and imaging techniques to systemically compare the effect of deafness-linked Cx mutations on GJ-mediated ionic and biochemical coupling. We found that several deafness-linked Cx26 (A84L, V95M, and A88S) and Cx30 (T5M) mutants specifically altered the permeation of GJs for molecules larger than simple ions [IP 3 , propidium iodide (PI)]. By using long-term organotypic cochlear cultures in which supporting cells were confirmed to be coupled by GJs, we demonstrated that intercellular biochemical coupling in the cochlea-mediated IP 3 diffusion initiated Ca 2ϩ waves, which is one type of long-range intercellular signaling known to contribute to many important cellular homeostatic processes (14).…”

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confidence: 99%

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Gap junction-mediated intercellular biochemical coupling in cochlear supporting cells is required for normal cochlear functions

Zhang

Tang²,

Ahmad³

et al. 2005

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

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134

136

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Dysfunction of gap junctions (GJs) caused by mutations in connexin26 (Cx26) and Cx30 accounts for nearly half of all cases of hereditary nonsyndromic deafness cases. Although it is widely held that GJs connecting supporting cells in the organ of Corti mainly provide ionic pathways for rapid removal of K ؉ around the base of hair cells, the function of GJs in the cochlea remains unknown. Here we show that GJs were not assembled in the supporting cells of the organ of Corti until 3 days after birth in mice and then gradually matured to connect supporting cells before the onset of hearing. In organotypic cochlear cultures that were confirmed to express GJs, GJs mediated the propagation of intracellular Ca 2؉ concentration waves in supporting cells by allowing intercellular diffusion of inositol 1,4,5-trisphosphate. We found that a subset of structurally mild Cx26 mutations located at the second transmembrane region (V84L, V95M, and A88S) and a Cx30 mutation located at the first cytoplasmic segment (T5M) specifically affect the intercellular exchange of larger molecules but leave the ionic permeability intact. Our results indicated that Cx26 and Cx30 mutations that are linked to sensorineural deafness retained ionic coupling but were deficient in biochemical permeability. Therefore, GJ-mediated intercellular exchange of biochemically important molecules is required for normal cochlear functions.connexin ͉ deafness ͉ mutation

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“…13,14 In mice, Cx26 and Cx30, apparently the two most abundantly expressed Cxs, are known to co-assemble to form GJ in the cochlea. 15 Mutations of GJB2, which encodes the Cx26 protein, and GJB6, which encodes the Cx30 protein, are implicated in cases of inherited nonsyndromic hearing loss. 1 In addition, Cx26 and Cx30 also co-assemble to form heteromeric GJ, and Cx26 mutant protein has dominant-negative effects on Cx30 protein.…”

Section: Introductionmentioning

confidence: 99%

Mutation R184Q of connexin 26 in hearing loss patients has a dominant-negative effect on connexin 26 and connexin 30

Su¹,

et al. 2010

Eur J Hum Genet

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Hearing impairment is the most common sensory disorder worldwide. In a recent study, the authors have shown that a heterozygous missense mutation, p.R184Q, in the connexin 26 (Cx26) is causally related to hearing loss. However, the functional change in the Cx26R184Q mutant remains unknown. This study compared the intracellular distribution and assembly of mutant Cx26R184Q with that of the wild-type (WT) Cx26 and Cx30WT in tet-on HeLa cells and the effect that the mutant protein had on those cells. Fluorescent localization assay of WT Cx26 showed the typical punctuate pattern of gap junction channel between neighboring expression cells. Conversely, the p.R184Q missense mutation resulted in accumulation of the Cx26 mutant protein in the Golgi apparatus rather than in the cytoplasmic membrane. Cx26R184Q coexpressed with either Cx26WT or Cx30WT showed perinuclear localization by bidirectional tet-on expression system, suggesting the impairment of the ability of both WT proteins to intracellular trafficking and targeting to the plasma membrane. Therefore, we proposed that Cx26R184Q has a dominant-negative effect on the function of WT Cx26 and Cx30.

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Connexins 26 and 30 are co-assembled to form gap junctions in the cochlea of mice

Cited by 181 publications

References 26 publications

Immunocytochemical Traits of Type IV Fibrocytes and Their Possible Relations to Cochlear Function and Pathology

Immunocytochemical Traits of Type IV Fibrocytes and Their Possible Relations to Cochlear Function and Pathology

Gap junction-mediated intercellular biochemical coupling in cochlear supporting cells is required for normal cochlear functions

Mutation R184Q of connexin 26 in hearing loss patients has a dominant-negative effect on connexin 26 and connexin 30

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