ArticleThe Journal of general physiology2010
Differentially altered Ca2+ regulation and Ca2+ permeability in Cx26 hemichannels formed by the A40V and G45E mutations that cause keratitis ichthyosis deafness syndrome.
Article in The Journal of general physiology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 97 papers.
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Who cites it
97 citing papers in PubMed, 136 citations in OpenAlex.
- The Unexplored Role of Connexin Hemichannels in Promoting Facioscapulohumeral Muscular Dystrophy Progression.International journal of molecular sciences · 2025Review
- Model-based evaluation of connexin hemichannel permeability.Computational and structural biotechnology journal · 2025Article
- The Role of Calcium Signaling in Sensorineural Hearing Loss.International journal of medical sciences · 2025Review
- An Ala/Glu difference in E1 of Cx26 and Cx30 contributes to their differential anionic permeabilities.The Journal of general physiology · 2024Article
- A pore locus in the E1 domain differentially regulates Cx26 and Cx30 hemichannel function.The Journal of general physiology · 2024Article
- Calcium Regulation of Connexin Hemichannels.International journal of molecular sciences · 2024Review
- Purification, Reconstitution, and Functional Analysis of Connexin Hemichannels.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Generation of Connexin-Expressing Stable Cell Pools.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Connexins in epidermal health and diseases: insights into their mutations, implications, and therapeutic solutions.Frontiers in physiology · 2024Review
- Functional Consequences of Pathogenic Variants of theBiomolecules · 2023Review
- Connexins in Cancer, the Possible Role of Connexin46 as a Cancer Stem Cell-Determining Protein.Biomolecules · 2023Review
- A Quantitative Assay for CaInternational journal of molecular sciences · 2022Article
- Extracellular Cysteines Are Critical to Form Functional Cx46 Hemichannels.International journal of molecular sciences · 2022Article
- Conformational changes and COStructure (London, England : 1993) · 2022Article
- Expression of KID syndromic mutation Cx26S17F produces hyperactive hemichannels in supporting cells of the organ of Corti.Frontiers in cell and developmental biology · 2022Article
- Connexin hemichannel inhibition ameliorates epidermal pathology in a mouse model of keratitis ichthyosis deafness syndrome.Scientific reports · 2021Article
- Cryo-EM structure of an open conformation of a gap junction hemichannel in lipid bilayer nanodiscs.Structure (London, England : 1993) · 2021Article
- Role of ROS/RNS in Preeclampsia: Are Connexins the Missing Piece?International journal of molecular sciences · 2020Review
- Microarray-based screening system identifies temperature-controlled activity of Connexin 26 that is distorted by mutations.Scientific reports · 2019Article
- Cx26 keratitis ichthyosis deafness syndrome mutations trigger alternative splicing of Cx26 to prevent expression and cause toxicityRoyal Society open science · 2019Article
37 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
Mutations in GJB2, which encodes Cx26, are one of the most common causes of inherited deafness in humans. More than 100 mutations have been identified scattered throughout the Cx26 protein, most of which cause nonsyndromic sensorineural deafness. In a subset of mutations, deafness is accompanied by hyperkeratotic skin disorders, which are typically severe and sometimes fatal. Many of these syndromic deafness mutations localize to the amino-terminal and first extracellular loop (E1) domains. Here, we examined two such mutations, A40V and G45E, which are positioned near the TM1/E1 boundary and are associated with keratitis ichthyosis deafness (KID) syndrome. Both of these mutants have been reported to form hemichannels that open aberrantly, leading to "leaky" cell membranes. Here, we quantified the Ca(2+) sensitivities and examined the biophysical properties of these mutants at macroscopic and single-channel levels. We find that A40V hemichannels show significantly impaired regulation by extracellular Ca(2+), increasing the likelihood of aberrant hemichannel opening as previously suggested. However, G45E hemichannels show only modest impairment in regulation by Ca(2+) and instead exhibit a substantial increase in permeability to Ca(2+). Using cysteine substitution and examination of accessibility to thiol-modifying reagents, we demonstrate that G45, but not A40, is a pore-lining residue. Both mutants function as cell-cell channels. The data suggest that G45E and A40V are hemichannel gain-of-function mutants that produce similar phenotypes, but by different underlying mechanisms. A40V produces leaky hemichannels, whereas G45E provides a route for excessive entry of Ca(2+). These aberrant properties, alone or in combination, can severely compromise cell integrity and lead to increased cell death.
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