Gap junctions and connexins in the inner ear: their roles in homeostasis and deafness

Abstract

Despite recent advances, a better understanding of the complexity 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.

The Membrane Properties of Cochlear Root Cells are Consistent with Roles in Potassium Recirculation and Spatial Buffering

“…This maintenance ensures the longevity of sensory hair cells and the generation of the endocochlear potential. The ion transporting mechanisms that regulate these concentrations have been characterized in a number of cochlear tissues, leading to widely held hypotheses of K + "recirculation" and "spatial buffering" (Forge et al 2003a;Hibino and Kurachi 2006;Kikuchi et al 2000;Kikuchi et al 1995;Nickel and Forge 2008;Nin et al 2008;Spicer and Schulte 1996;Takeuchi et al 2000;Wangemann 2006;Weber et al 2001;. In common with these mechanisms studied in the CNS and retina (Kofuji and Newman 2004), cochlear K + recirculation and spatial buffering both rely on gap junctional coupling throughout the epithelial cell network, and the ability of cells at the edges of the network to secrete K + .…”

Reduced Electromotility of Outer Hair Cells Associated with Connexin-Related Forms of Deafness: An In silico Study of a Cochlear Network Mechanism

“…It is well known that a functional epithelial cell gap junction system is essential for normal development of the inner ear as it facilitates necessary intercellular signalling (Nickel and Forge 2008). It is therefore not surprising that some GJ mutations lead to developmental malformations of the organ of Corti.…”

“…Mutations in a single gene, the gap junction beta 2 (GJB2) gene, account for nearly 50% of cases. The GJB2 gene encodes for the protein connexin 26 (Cx26), which together with other connexins such as Cx30, forms the gap junctions between non-sensory cells in the cochlea (for review, see Nickel and Forge 2008;Rabionet et al 2000). The most common GJB2 mutations are single nucleotide deletions and frame shifts (such as 35delG, 167delT, and 235delC).…”

“…Gap junctions constitute two major systems of intercellular communication in the cochlea: the epithelial cell gap junction system coupling supporting cells in the organ of Corti and the connective tissue gap junction system connecting the type 2 fibrocytes in the spiral ligament with basal and intermediate cells in the stria vascularis (Nickel and Forge 2008;Zhao et al 2006). It is widely held that the passage of ions, mainly K + from scala media, generates electrical currents in the cochlear partition upon the activation by sound of the mechanotransducer (MET) channels in hair cells ( Figure 1A).…”

Mutations in Cx30 that are linked to skin disease and non-syndromic hearing loss exhibit several distinct cellular pathologies

“…In the cochlea, Cx26, Cx29, Cx30, Cx31 and Cx43, found in the epithelial and connective tissue gap junction networks, play a crucial role in sound transduction. Cx26, and possibly other connexins, are thought to be involved in the recycling of K + through the supporting cells back to the endolymphatic space, for potential re-entry into sensory cells when activated by an acoustic stimulus (Kikuchi et al, 2000;Nickel and Forge, 2008). Interestingly, at least seven connexins, including Cx26, Cx30 and Cx43, are temporally and spatially expressed at the protein level in the human epidermis with overlapping distribution in the various non-cornified epidermal strata (Di et al, 2001;Kretz et al, 2004).…”