ArticleThe Journal of general physiology2018
The syndromic deafness mutation G12R impairs fast and slow gating in Cx26 hemichannels.
Article in The Journal of general physiology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Model-based evaluation of connexin hemichannel permeability.Computational and structural biotechnology journal · 2025Article
- Large-pore connexin hemichannels function like molecule transporters independent of ion conduction.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Genetically engineered human embryonic kidney cells as a novel vehicle for dual patch clamp study of human gap junction channels.The Biochemical journal · 2024Article
- Calcium Regulation of Connexin Hemichannels.International journal of molecular sciences · 2024Review
- Connexin channels and hemichannels are modulated differently by charge reversal at residues forming the intracellular pocket.Biological research · 2024Article
- Connexin Gap Junction Channels and Hemichannels: Insights from High-Resolution Structures.Biology · 2024Review
- Functional Consequences of Pathogenic Variants of theBiomolecules · 2023Review
- Simulation-predicted and -explained inheritance model of pathogenicity confirmed by transgenic mice models.Computational and structural biotechnology journal · 2023Article
- 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
- Cellular mechanisms of connexin-based inherited diseases.Trends in cell biology · 2022Review
- Dysregulation of Connexin Expression Plays a Pivotal Role in Psoriasis.International journal of molecular sciences · 2021Article
- The Complex and Critical Role of Glycine 12 (G12) in Beta-Connexins of Human Skin.International journal of molecular sciences · 2021Review
- A novel voltage-clamp/dye uptake assay reveals saturable transport of molecules through CALHM1 and connexin channels.The Journal of general physiology · 2020Article
- Connexin-46/50 in a dynamic lipid environment resolved by CryoEM at 1.9 Å.Nature communications · 2020Article
- Calmodulin-Mediated Regulation of Gap Junction Channels.International journal of molecular sciences · 2020Review
- The connexin26 human mutation N14K disrupts cytosolic intersubunit interactions and promotes channel opening.The Journal of general physiology · 2019Article
- Electrical coupling and its channels.The Journal of general physiology · 2018Review
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11 authors.
Funding
Abstract
Mutations in connexin 26 (Cx26) hemichannels can lead to syndromic deafness that affects the cochlea and skin. These mutations lead to gain-of-function hemichannel phenotypes by unknown molecular mechanisms. In this study, we investigate the biophysical properties of the syndromic mutant Cx26G12R (G12R). Unlike wild-type Cx26, G12R macroscopic hemichannel currents do not saturate upon depolarization, and deactivation is faster during hyperpolarization, suggesting that these channels have impaired fast and slow gating. Single G12R hemichannels show a large increase in open probability, and transitions to the subconductance state are rare and short-lived, demonstrating an inoperative fast gating mechanism. Molecular dynamics simulations indicate that G12R causes a displacement of the N terminus toward the cytoplasm, favoring an interaction between R12 in the N terminus and R99 in the intracellular loop. Disruption of this interaction recovers the fast and slow voltage-dependent gating mechanisms. These results suggest that the mechanisms of fast and slow gating in connexin hemichannels are coupled and provide a molecular mechanism for the gain-of-function phenotype displayed by the syndromic G12R mutation.
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