The Cx26-G45E mutation displays increased hemichannel activity in a mouse model of the lethal form of keratitis-ichthyosis-deafness syndrome

Meşe, Gülistan; Sellitto, Caterina; Li, Leping; Wang, Hong-Zhan; Valiūnas, Virginijus; Richard, Gabriele; Brink, Peter R.; White, Thomas W.

doi:10.1091/mbc.e11-09-0778

Cited by 84 publications

(113 citation statements)

References 72 publications

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“…Connexin hemichannels have long been considered as merely structural precursors, yet compelling evidence in the last few years clearly shows that hemichannels autonomously form a pathway of communication, albeit not between neighboring cells, as is the case for gap junctions, but between the cytosol of individual cells and their extracellular environment. In fact, not only dysregulated gap junctional communication, but also aberrant connexin hemichannel activity has been observed in a number of skin diseases [28][29][30][31]. Several authors have reported Cx43 modulation in human diseases related to poor skin healing, such as hypertrophic scars and keloids [11] or in wounds of diabetic patients [32,33].…”

Section: Discussionmentioning

confidence: 99%

Connexin 43 deficiency accelerates skin wound healing and extracellular matrix remodeling in mice

Cogliati

Vinken

Silva

et al. 2015

Journal of Dermatological Science

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Background Cellular channels composed of connexin 43 are known to act as key players in the life cycle of the skin and consequently to underlie skin repair. Objective This study was specifically set up to investigate the suite of molecular mechanisms driven by connexin 43-based channels on wound healing. Methods To this end, a battery of parameters, including re-epithelialization, neovascularization, collagen deposition and extracellular matrix remodeling, was monitored over time during experimentally induced skin repair in heterozygous connexin 43 knockout mice. Results It was found that connexin 43 deficiency accelerates re-epithelialization and wound closure, increases proliferation and activation of dermal fibroblasts, and enhances the expression of extracellular matrix remodeling mediators. Conclusion These data substantiate the notion that connexin 43 may represent an interesting therapeutic target in dermal wound healing.

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Section: Discussionmentioning

confidence: 99%

Connexin 43 deficiency accelerates skin wound healing and extracellular matrix remodeling in mice

Cogliati

Vinken

Silva

et al. 2015

Journal of Dermatological Science

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“…Communication deficient HeLa cells were plated on 22-mm 2 coverslips, grown to 50% confluence, and transiently transfected with wild-type Cx26, Cx26-D50A, or Cx26-A88V in pIRES2-EGFP2 using Lipofectamine 2000 (Invitrogen, Carlsbad, CA) as previously described (29,30) with the exception that calcium concentrations in the tissue culture media were elevated to a final concentration of 4 mM with supplemental CaCl 2. Primary human keratinocytes were obtained from the Living Skin Bank (Stony Brook University, Stony Brook, NY) and cultured in KGM-Gold keratinocyte growth medium (Lonza, Walkersville, MD).…”

Section: Methodsmentioning

confidence: 99%

“…To obtain hemichannel current-voltage (I-V) curves, cells were initially clamped at Ϫ40 mV and subjected to 5-s depolarizing voltage steps ranging from Ϫ30 to ϩ60 mV in 10-mV increments (21). Electrophysiological measurements in transfected HeLa cells or primary human keratinocytes were carried out using whole cell patch clamp at room temperature as previously described (29,30). At the beginning of each experiment, cells were clamped at 0 mV and then stepped for 2-s intervals to different voltages (Ϫ110 to ϩ110 mV in 20-mV increments).…”

Section: Methodsmentioning

confidence: 99%

The human Cx26-D50A and Cx26-A88V mutations causing keratitis-ichthyosis-deafness syndrome display increased hemichannel activity

Mhaske

Levit

et al. 2013

American Journal of Physiology-Cell Physiology

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Mutations in the human gene encoding connexin 26 (Cx26 or GJB2) cause either nonsyndromic deafness or syndromic deafness associated with skin diseases. That distinct clinical disorders can be caused by different mutations within the same gene suggests that different channel activities influence the ear and skin. Here we use three different expression systems to examine the functional characteristics of two Cx26 mutations causing either mild (Cx26-D50A) or lethal (Cx26-A88V) keratitis-ichthyosis-deafness (KID) syndrome. In either cRNA-injected Xenopus oocytes, transfected HeLa cells, or transfected primary human keratinocytes, we show that both Cx26-D50A and Cx26-A88V form active hemichannels that significantly increase membrane current flow compared with wild-type Cx26. This increased membrane current accelerated cell death in low extracellular calcium solutions and was not due to increased mutant protein expression. Elevated mutant hemichannel currents could be blocked by increased extracellular calcium concentration. These results show that these two mutations exhibit a shared gain of functional activity and support the hypothesis that increased hemichannel activity is a common feature of human Cx26 mutations responsible for KID syndrome.

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“…Cx30 forms voltage-gated hemichannels (Valiunas and Weingart, 2000), which are normally closed under physiological conditions and open in response to low extracellular concentrations of Ca 2+ and Mg 2+ (De Vuyst et al, 2007;Tong et al, 2007;Verselis and Srinivas, 2008). Importantly, leaky hemichannels that result in cell death have been reported for a number of other connexin mutations (Gerido et al, 2007;Lee et al, 2009;Mese et al, 2011;Stong et al, 2006) and also for the A88V Cx26 mutation, which is linked to KID syndrome (Mhaske et al, 2013). The crystal structure of Cx26 suggests that part of the…”

Section: The A88v Mutant Linked To Clouston Syndromementioning

confidence: 99%

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

Berger

Kelly

Lajoie

et al. 2014

Journal of Cell Science

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Connexin 30 (Cx30), a member of the large gap junction protein family, plays a role in the homeostasis of the epidermis and inner ear through gap junctional intercellular communication (GJIC). Here, we investigated the underlying mechanisms of four autosomal dominant Cx30 gene mutations linked to hearing loss and/or various skin diseases. First, the T5M mutant linked to non-syndromic hearing loss formed functional gap junction channels and hemichannels, similar to wild type Cx30. The loss-of-function V37E mutant associated with Clouston syndrome or keratitis-ichthyosis-deafness syndrome was retained in the endoplasmic reticulum and significantly induced apoptosis. The G59R mutant linked to Vohwinkel and Bart-Pumphrey syndromes was retained primarily in the Golgi apparatus and exhibited loss of gap junction channel and hemichannel function, but did not cause cell death. Lastly, the A88V mutant related to Clouston syndrome also significantly induced apoptosis, although through an endoplasmic reticulum-independent mechanism. Collectively, we discovered that four unique Cx30 mutants may cause disease through different mechanisms that also likely include their selective transdominant effects on co-expressed connexins, highlighting the overall complexity of connexin-linked diseases and the importance of GJIC in disease prevention.

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The Cx26-G45E mutation displays increased hemichannel activity in a mouse model of the lethal form of keratitis-ichthyosis-deafness syndrome

Cited by 84 publications

References 72 publications

Connexin 43 deficiency accelerates skin wound healing and extracellular matrix remodeling in mice

Connexin 43 deficiency accelerates skin wound healing and extracellular matrix remodeling in mice

The human Cx26-D50A and Cx26-A88V mutations causing keratitis-ichthyosis-deafness syndrome display increased hemichannel activity

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

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