ArticleThe Journal of biological chemistry2014
Altered inhibition of Cx26 hemichannels by pH and Zn2+ in the A40V mutation associated with keratitis-ichthyosis-deafness syndrome.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 40 citations in OpenAlex.
- Connexin 26 in Hearing Health and Disease: StructuralFoundations, Mutation Mechanisms, and Therapeutic Perspectives.International journal of molecular sciences · 2026Review
- Reversible lipid-mediated pH-gating of connexin-46/50 by cryo-EM.Nature communications · 2026Article
- Cellular mechanisms of connexin-based inherited diseases.Trends in cell biology · 2022Review
- Cryo-EM structure of an open conformation of a gap junction hemichannel in lipid bilayer nanodiscs.Structure (London, England : 1993) · 2021Article
- Mechanisms Underlying Connexin Hemichannel Activation in Disease.International journal of molecular sciences · 2021Review
- Review
- Astroglial Connexins in Neurodegenerative Diseases.Frontiers in molecular neuroscience · 2021Review
- A Steric "Ball-and-Chain" Mechanism for pH-Mediated Regulation of Gap Junction Channels.Cell reports · 2020Article
- Calmodulin-Mediated Regulation of Gap Junction Channels.International journal of molecular sciences · 2020Review
- Inner Ear Connexin Channels: Roles in Development and Maintenance of Cochlear Function.Cold Spring Harbor perspectives in medicine · 2019Review
- A Human-Derived Monoclonal Antibody Targeting Extracellular Connexin Domain Selectively Modulates Hemichannel Function.Frontiers in physiology · 2019Article
- Connexins and Disease.Cold Spring Harbor perspectives in biology · 2018Review
- Cues to Opening Mechanisms FromFrontiers in molecular neuroscience · 2018Article
- Gap junction structure: unraveled, but not fully revealed.F1000Research · 2017Review
- Design and Characterization of a Human Monoclonal Antibody that Modulates Mutant Connexin 26 Hemichannels Implicated in Deafness and Skin Disorders.Frontiers in molecular neuroscience · 2017Article
- Altered CO2 sensitivity of connexin26 mutant hemichannels in vitro.Physiological reports · 2016Article
- Structural studies of N-terminal mutants of Connexin 26 and Connexin 32 using (1)H NMR spectroscopy.Archives of biochemistry and biophysics · 2016Article
- Syndromic deafness mutations at Asn 14 differentially alter the open stability of Cx26 hemichannels.The Journal of general physiology · 2016Article
- Connexinopathies: a structural and functional glimpse.BMC cell biology · 2016Review
- Gap-junctional channel and hemichannel activity of two recently identified connexin 26 mutants associated with deafness.Pflugers Archiv : European journal of physiology · 2016Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Excessive opening of undocked Cx26 hemichannels in the plasma membrane is associated with disease pathogenesis in keratitis-ichthyosis-deafness (KID) syndrome. Thus far, excessive opening of KID mutant hemichannels has been attributed, almost solely, to aberrant inhibition by extracellular Ca(2+). This study presents two new possible contributing factors, pH and Zn(2+). Plasma pH levels and micromolar concentrations of Zn(2+) inhibit WT Cx26 hemichannels. However, A40V KID mutant hemichannels show substantially reduced inhibition by these factors. Using excised patches, acidification was shown to be effective from either side of the membrane, suggesting a protonation site accessible to H(+) flux through the pore. Sensitivity to pH was not dependent on extracellular aminosulfonate pH buffers. Single channel recordings showed that acidification did not affect unitary conductance or block the hemichannel but rather promoted gating to the closed state with transitions characteristic of the intrinsic loop gating mechanism. Examination of two nearby KID mutants in the E1 domain, G45E and D50N, showed no changes in modulation by pH or Zn(2+). N-bromo-succinimide, but not thiol-specific reagents, attenuated both pH and Zn(2+) responses. Individually mutating each of the five His residues in WT Cx26 did not reveal a key His residue that conferred sensitivity to pH or Zn(2+). From these data and the crystal structure of Cx26 that suggests that Ala-40 contributes to an intrasubunit hydrophobic core, the principal effect of the A40V mutation is probably a perturbation in structure that affects loop gating, thereby affecting multiple factors that act to close Cx26 hemichannels via this gating mechanism.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.