The role of connexins in ear and skin physiology — Functional insights from disease-associated mutations

Abstract

Defects in several different connexins have been associated with several different diseases. The most common of these is deafness, where a few mutations in connexin (Cx) 26 have been found to contribute to over 50% of the incidence of non-syndromic deafness in different human populations. Other mutations in Cx26 or Cx30 have also been associated with various skin phenotypes linked to deafness (PPK, BPS, VS, KID, etc.). The large array of disease mutants offer unique opportunities to gain insights into the underlying function of gap junction proteins and their channels in the normal and pathogenic physiology of the cochlea and epidermis. This review focuses on those mutants where the impact on channel function has been assessed, and correlated with the disease phenotype, or organ function in knock-out mouse models. These approaches have provided evidence supporting a role of gap junctions and hemichannels in K+ removal and recycling in the ear, as well as possible roles for nutrient passage, in the cochlea. In contrast, increases in hemichannel opening leading to increased cell death, was associated with several KID skin disease/hearing mutants. In addition to providing clues for therapeutic strategies, these findings allow us to better understand the specific functions of connexin channels that are important for normal tissue function.

Vestibular Functions of Hereditary Hearing Loss Patients with <b><i>GJB2</i></b> Mutations

“…The expression of GJB2 has been documented in a variety of cells and tissues. In the cochlea, Cx26-containing gap junctions are proposed to maintain cochlear homeostasis and the circulation of metabolites, such as inositol 1,4, 5-trisphosphate, which is critical for cellular function and the survival of cochlea-supporting cells [Kikuchi et al, 1995;Martinez et al, 2009;Xu and Nicholson, 2013].…”

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

“…Connexin 30 (Cx30; also known as GJB6) is specifically expressed in skin keratinocytes (Di et al, 2001), brain astrocytes (Dahl et al, 1996), retinal astrocytes (Mansour et al, 2013) and various inner ear cell types (Forge et al, 2003a). Mutations in the Cx30-encoding gene GJB6 cause skin disease or hearing loss, or a combination of both (Xu and Nicholson, 2013), suggesting an essential role for Cx30 in these systems.…”

Mechanism of gating by calcium in connexin hemichannels

“…It is widely accepted that hyperactive connexin hemichannels play pathological roles. For instance, several human connexin mutations that cause human pathologies produce exacerbated hemichannel activity at the plasma membrane, which has deleterious consequences (3)(4)(5). Similarly, in nongenetic pathologies, including ischemia and muscular dystrophy, there is strong evidence that opening of hemichannels enhances tissue damage (6)(7)(8).…”