Drowning out communication. Focus on "The human Cx26-D50A and Cx26-A88V mutations causing keratitis-ichthyosis-deafness syndrome display increased hemichannel activity".

GAP JUNCTIONS PROVIDE A PATHWAY for intercellular communication primarily by directly interconnecting the cytoplasm of adjacent cells (3). This pathway consists of arrays of channels, composed of proteins known as connexins. Connexin channels create a direct conduit enabling diffusion of cytoplasmic molecules, ions, and water between cells. Gap junctions thus coordinate signaling and metabolism between otherwise disconnected cells within a tissue. A complete gap junction channel consists of two hexamers, one on each cell, docked to each other and organized into plaques (Figure 1). There are two dozen human connexin genes. Different tissues express different connexins, which, in turn, produce channels with different composition, permeability, and regulation. In this way, gap junctional communication is controlled. Conversely, misregulation of intercellular communication, due to mutations that cause a loss or alteration of connexin function, has the capacity to cause human disease (3). Connexin 26 (Cx26) is critical for hearing; several mutations that inhibit Cx26 channel function impair cochlear potassium homeostasis and cause deafness (10). However, Cx26 mutations are implicated in a spectrum of diseases ranging from nonsyndromic hearing loss to diseases affecting multiple organ systems. In this issue of American Journal of Physiology-Cell Physiology, Mhaske et al. (5) characterized two Cx26 mutations (D50A and A88V) associated with keratitis-ichthyosisdeafness (KID) syndrome, which is a disease that disrupts the eye and skin barriers as well as causes deafness. They found that instead of simply inhibiting channel formation, these mutations produced forms of Cx26 that formed high conductance hemichannels at the cell surface. “Gain of function” Cx26 mutations thus create channels that have more generalized toxicity than mutations that lead to nonfunctional Cx26, which, more typically, are limited to affecting cochlear function. Other KID-associated Cx26 mutations have a comparable effect on hemichannel permeability, suggesting a unifying mechanism linking this particular deafness associated mutation with skin disease (10). In each case, KID-associated mutations in Cx26 affected conductance but had less of an effect on spontaneous open probability. In other words, the channels still required a stimulus to open, but channels containing mutant Cx26 were more permeable than wild-type Cx26. Despite comparable open probabilities, the high permeability of hemichannels composed of mutant Cx26 facilitates leakage of critical metabolites and leads to cell death. Importantly, KID mutants of Cx26 exhibit a similar effect when transfected into normal human keratinocytes and had a dominant negative effect on wild-type Cx26 (5). Specifically, the D50A and A88V Cx26 mutations inhibited the trafficking