Connexin hemichannels influence genetically determined inflammatory and hyperproliferative skin diseases

Levit, Noah A.; White, Thomas W.

doi:10.1016/j.phrs.2015.07.015

Cited by 13 publications

(15 citation statements)

References 148 publications

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“…Interestingly, mutation of the A88 residue to serine, which does not cause KID syndrome, only has recessive and modest effects on CO 2 sensitivity. The main hypothesis for the effects of the dominant missense mutations of Cx26 causing syndromes is that there is a gain of functionthrough increased hemichannel activity (Levit et al 2014;Levit and White 2015;Lilly et al 2016). Our data now provide an alternative or additional potential hypothesisthat the loss of CO 2 -dependent modulation of hemichannel gating could contribute to pathology, at least for some mutations of Cx26.…”

Section: Implications For Etiology Of Kid Syndromementioning

confidence: 70%

Altered CO₂ sensitivity of connexin26 mutant hemichannels in vitro

et al. 2016

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Connexin26 (Cx26) mutations underlie human pathologies ranging from hearing loss to keratitis ichthyosis deafness (KID) syndrome. Cx26 hemichannels are directly gated by CO 2 and contribute to the chemosensory regulation of breathing. The KID syndrome mutation A88V is insensitive to CO 2, and has a dominant negative action on the CO 2 sensitivity of Cx26WT hemichannels, and reduces respiratory drive in humans. We have now examined the effect of further human mutations of Cx26 on its sensitivity to CO 2 . Mutated Cx26 subunits, carrying one of A88S, N14K, N14Y, M34T, or V84L, were transiently expressed in HeLa cells. The CO 2‐dependence of hemichannel activity, and their ability to exert dominant negative actions on cells stably expressing Cx26WT, was quantified by a dye‐loading assay. The KID syndrome mutation, N14K, abolished the sensitivity of Cx26 to CO 2. Both N14Y and N14K exerted a powerful dominant negative action on the CO 2 sensitivity of Cx26WT. None of the other mutations (all recessive) had a dominant negative action. A88S shifted the affinity of Cx26 to slightly higher levels without reducing its ability to fully open to CO 2. M34T did not change the affinity of Cx26 for CO 2 but reduced its ability to open in response to CO 2. V84L had no effect on the CO 2‐sensitivity of Cx26. Some pathological mutations of Cx26 can therefore alter the CO 2 sensitivity of Cx26 hemichannels. The loss of CO 2 sensitivity could contribute to pathology and consequent reduced respiratory drive could be an unrecognized comorbidity of these pathologies.

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Section: Implications For Etiology Of Kid Syndromementioning

confidence: 70%

Altered CO₂ sensitivity of connexin26 mutant hemichannels in vitro

et al. 2016

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“…Recently, reported that HCs formed by expression of several Cx26 KID mutants in Xenopus laevis oocytes are inhibited by mefloquine (IC 50 w 16 mM). It needs to be investigated whether specific inhibitory compounds for Cx HC can be used to repress the inflammatory and septic features of KID mutations in the skin of mouse models and eventually in patients with KID (Levit and White, 2015).…”

Section: Comparison Of Kid Mouse Models and Patients With Kidmentioning

confidence: 99%

From Hyperactive Connexin26 Hemichannels to Impairments in Epidermal Calcium Gradient and Permeability Barrier in the Keratitis-Ichthyosis-Deafness Syndrome

García

Bosen

Mujica

et al. 2016

Journal of Investigative Dermatology

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The keratitis-ichthyosis-deafness (KID) syndrome is characterized by corneal, skin, and hearing abnormalities. KID has been linked to heterozygous dominant missense mutations in the GJB2 and GJB6 genes, encoding connexin26 and 30, respectively. In vitro evidence indicates that KID mutations lead to hyperactive (open) hemichannels, which in some cases is accompanied by abnormal function of gap junction channels. Transgenic mouse models expressing connexin26 KID mutations reproduce human phenotypes and present impaired epidermal calcium homeostasis and abnormal lipid composition of the stratum corneum affecting the water barrier. Here we have compiled relevant data regarding the KID syndrome and propose a mechanism for the epidermal aspects of the disease.

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“…Dominant Cx26 mutations underlying syndromic deafness associated with severe often fatal skin disorders exemplified by keratitis-ichthyosis-deafness (KID) syndrome, Vohwinkel syndrome, and Bart-Pumphrey syndrome are less common. 25 syndromic mutations have been identified, most of which map to the N-terminus and to the region of the channel pore formed by the first transmembrane helix (TM1) and first extracellular loop (E1) [12, 13]. Mutations of Cx32 cause X-linked Charcot-Marie-Tooth (CMT-X) disease, a late onset peripheral neuropathy [14], which in some cases has central nervous system involvement [15, 16].…”

Section: Introductionmentioning

confidence: 99%

Structural studies of N-terminal mutants of Connexin 26 and Connexin 32 using 1H NMR spectroscopy

Batir

Bargiello

Dowd

2016

Archives of Biochemistry and Biophysics

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Alterations in gap junctions underlie the etiologies of syndromic deafness (KID) and Charcot-Marie Tooth disease (CMTX). Functional gap junctions are composed of connexin molecules with N-termini containing a flexible turn around G12, inserting the N-termini into the channel pore allowing voltage gating. The loss of this turn correlates with loss of Connexin 32 (Cx32) function by impaired trafficking to the cell membrane. Using 1H NMR we show the N-terminus of a syndromic deafness mutation Cx26G12R, producing “leaky channels”, contains a turn around G12 which is less structured and more flexible than wild-type. In contrast, the N-terminal structure of the same mutation in Cx32 chimera, Cx32*43E1G12R shows a larger constricted turn and no membrane current expression but forms membrane inserted hemichannels. Their function was rescued by formation of heteromeric channels with wild type subunits. We suggest the inflexible Cx32G12R N-terminus blocks ion conduction in homomeric channels and this channel block is relieved by incorporation of wild type subunits. In contrast, the increased open probability of Cx26G12R hemichannels is likely due to the addition of positive charge in the channel pore changing pore electrostatics and impairing hemichannel regulation by Ca2+. These results provide mechanistic information on aberrant channel activity observed in disease.

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Connexin hemichannels influence genetically determined inflammatory and hyperproliferative skin diseases

Cited by 13 publications

References 148 publications

Altered CO₂ sensitivity of connexin26 mutant hemichannels in vitro

Altered CO₂ sensitivity of connexin26 mutant hemichannels in vitro

From Hyperactive Connexin26 Hemichannels to Impairments in Epidermal Calcium Gradient and Permeability Barrier in the Keratitis-Ichthyosis-Deafness Syndrome

Structural studies of N-terminal mutants of Connexin 26 and Connexin 32 using 1H NMR spectroscopy

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Connexin hemichannels influence genetically determined inflammatory and hyperproliferative skin diseases

Cited by 13 publications

References 148 publications

Altered CO2 sensitivity of connexin26 mutant hemichannels in vitro

Altered CO2 sensitivity of connexin26 mutant hemichannels in vitro

From Hyperactive Connexin26 Hemichannels to Impairments in Epidermal Calcium Gradient and Permeability Barrier in the Keratitis-Ichthyosis-Deafness Syndrome

Structural studies of N-terminal mutants of Connexin 26 and Connexin 32 using 1H NMR spectroscopy

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Altered CO₂ sensitivity of connexin26 mutant hemichannels in vitro

Altered CO₂ sensitivity of connexin26 mutant hemichannels in vitro