Connexins and gap junctions in the inner ear – it’s not just about K+ recycling

Jagger, Daniel J.; Forge, Andrew

doi:10.1007/s00441-014-2029-z

Cited by 89 publications

(88 citation statements)

References 109 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Classically, the connexin-based gap junction network in the adult cochlea is thought to contribute to cochlear homeostasis (Zdebik et al, 2009). Mouse models confirmed that Cx26 and Cx30 are involved in a wide range of activities important for the normal function of the developing and mature hearing system (Mammano, 2013; Jagger and Forge, 2015; Kelly et al, 2015; Wingard and Zhao, 2015; Zhu et al, 2015). …”

Section: Introductionmentioning

confidence: 83%

“…Cx26 and Cx30 are the predominant connexins in the mammalian cochlea and the only isoforms expressed in the sensory epithelium (Jagger and Forge, 2015; Wingard and Zhao, 2015). These connexins have been shown to form extrajunctional hemichannels (Anselmi et al, 2008; Majumder et al, 2010) and also to coassemble to form homomeric or heteromeric gap junction channels between nonsensory cells (Forge et al, 2003; Martínez et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…Current evidence indicates that Cx26 and Cx30 are crucial for maintaining the ionic and metabolic homeostasis of the inner ear and mediating intercellular signaling in the nonsensory epithelium (Mammano, 2013; Jagger and Forge, 2015; Wingard and Zhao, 2015). We now show that these connexins are also involved in the maturation of the biophysical and morphological properties of IHCs, which normally occurs at around the onset of hearing.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Connexin-Mediated Signaling in Nonsensory Cells Is Crucial for the Development of Sensory Inner Hair Cells in the Mouse Cochlea

et al. 2016

View full text Add to dashboard Cite

Mutations in the genes encoding for gap junction proteins connexin 26 (Cx26) and connexin 30 (Cx30) have been linked to syndromic and nonsyndromic hearing loss in mice and humans. The release of ATP from connexin hemichannels in cochlear nonsensory cells has been proposed to be the main trigger for action potential activity in immature sensory inner hair cells (IHCs), which is crucial for the refinement of the developing auditory circuitry. Using connexin knock-out mice, we show that IHCs fire spontaneous action potentials even in the absence of ATP-dependent intercellular Ca2+ signaling in the nonsensory cells. However, this signaling from nonsensory cells was able to increase the intrinsic IHC firing frequency. We also found that connexin expression is key to IHC functional maturation. In Cx26 conditional knock-out mice (Cx26Sox10-Cre), the maturation of IHCs, which normally occurs at approximately postnatal day 12, was partially prevented. Although Cx30 has been shown not to be required for hearing in young adult mice, IHCs from Cx30 knock-out mice exhibited a comprehensive brake in their development, such that their basolateral membrane currents and synaptic machinery retain a prehearing phenotype. We propose that IHC functional differentiation into mature sensory receptors is initiated in the prehearing cochlea provided that the expression of either connexin reaches a threshold level. As such, connexins regulate one of the most crucial functional refinements in the mammalian cochlea, the disruption of which contributes to the deafness phenotype observed in mice and DFNB1 patients.SIGNIFICANCE STATEMENT The correct development and function of the mammalian cochlea relies not only on the sensory hair cells, but also on the surrounding nonsensory cells. Although the nonsensory cells have been largely implicated in the general homeostasis in the mature cochlea, their involvement in the initial functional differentiation of the sensory inner hair cells is less clear. Using mutant mouse models for the most common form of congenital deafness in humans, which are knock-outs for the gap-junction channels connexin 26 and connexin 30 genes, we show that defects in nonsensory cells prevented the functional maturation of inner hair cells. In connexin knock-outs, inner hair cells remained stuck at a prehearing stage of development and, as such, are unable to process sound information.

show abstract

Section: Introductionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Connexin-Mediated Signaling in Nonsensory Cells Is Crucial for the Development of Sensory Inner Hair Cells in the Mouse Cochlea

et al. 2016

View full text Add to dashboard Cite

show abstract

“…In the inner ear, these large Cx30 gap junction plaques are found between supporting cells within the avascular organ of Corti (Sun et al, 2005;Jagger and Forge, 2006), which plays a key role in K + buffering and metabolite transfer (Jagger and Forge, 2014). Therefore, large gap junction plaques may be crucial for maintaining homeostasis by maximizing cell-cell transfer of metabolites and nutrients (Chang et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Cx30 exhibits unique characteristics including a long half-life when assembled into gap junctions

Kelly

Shao

Jagger

et al. 2015

Journal of Cell Science

Self Cite

View full text Add to dashboard Cite

show abstract

“…Additionally, mutations in GJB6 encoding Cx30 can also result in hearing impairment. Jagger and Forge (2015) argue that, whereas evidence exists that the gap junctions in the cochlea composed of these two connexins provide a pathway for direct cell to cell passage of K + ions to maintain the ionic environment necessary for sound perception and sensory cell survival, channels of almost any composition could allow K + transfer. Thus, the authors suggest that other connexin/gap junction roles might be affected by GJB2 or GJB6 mutation.…”

mentioning

confidence: 99%