ArticleThe Journal of biological chemistry2009
Loop gating of connexin hemichannels involves movement of pore-lining residues in the first extracellular loop domain.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers.
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Who cites it
64 citing papers in PubMed, 88 citations in OpenAlex.
- Diverse roles of connexins in the neuro-vasculature in homeostasis and disease.Translational neuroscience · 2026Review
- Model-based evaluation of connexin hemichannel permeability.Computational and structural biotechnology journal · 2025Article
- 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
- Connexin Gap Junction Channels and Hemichannels: Insights from High-Resolution Structures.Biology · 2024Review
- Simulation of gap junction formation reveals critical role of Cys disulfide redox state in connexin hemichannel docking.Cell communication and signaling : CCS · 2024Article
- Connexons Coupling to Gap Junction Channel: Potential Role for Extracellular Protein Stabilization Centers.Biomolecules · 2021Article
- Activation of Cx43 Hemichannels Induces the Generation of CaInternational journal of molecular sciences · 2021Article
- Article
- Lens Connexin Channels Show Differential Permeability to Signaling Molecules.International journal of molecular sciences · 2020Review
- Connexin-46/50 in a dynamic lipid environment resolved by CryoEM at 1.9 Å.Nature communications · 2020Article
- Electrical coupling and its channels.The Journal of general physiology · 2018Review
- LRRC8 N termini influence pore properties and gating of volume-regulated anion channels (VRACs).The Journal of biological chemistry · 2018Article
- The syndromic deafness mutation G12R impairs fast and slow gating in Cx26 hemichannels.The Journal of general physiology · 2018Article
- Gating of Connexin Channels by transjunctional-voltage: Conformations and models of open and closed states.Biochimica et biophysica acta. Biomembranes · 2018Review
- Permeant-specific gating of connexin 30 hemichannels.The Journal of biological chemistry · 2017Article
- Calcium binding and voltage gating in Cx46 hemichannels.Scientific reports · 2017Article
- Connexins in Cardiovascular and Neurovascular Health and Disease: Pharmacological Implications.Pharmacological reviews · 2017Review
- The NHAmerican journal of physiology. Cell physiology · 2017Article
- Accessing gap-junction channel structure-function relationships through molecular modeling and simulations.BMC cell biology · 2017Review
4 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Unapposed connexin hemichannels exhibit robust closure in response to membrane hyperpolarization and extracellular calcium. This form of gating, termed "loop gating," is largely responsible for regulating hemichannel opening, thereby preventing cell damage through excessive flux of ions and metabolites. The molecular components and structural rearrangements underlying loop gating remain unknown. Here, using cysteine mutagenesis in Cx50, we demonstrate that residues at the TM1/E1 border undergo movement during loop gating. Replacement of Phe(43) in Cx50 with a cysteine resulted in small or no appreciable membrane currents. Bath application of dithiothreitol or TPEN (N,N,N',N'-tetrakis(2-pyridylmethyl) ethylenediamine), reagents that exhibit strong transition metal chelating activity, led to robust currents indicating that the F43C substitution impaired hemichannel function, producing "lock-up" in a closed or poorly functional state due to formation of metal bridges. In support, Cd(2+) at submicromolar concentrations (50-100 nm) enhanced lock-up of F43C hemichannels. Moreover, lock-up occurred under conditions that favored closure, indicating that the sulfhydryl groups come close enough to each other or to other residues to coordinate metal ions with high affinity. In addition to F43C, metal binding was also found for G46C, and to a lesser extent, D51C substitutions, positions found to be pore-lining in the open state using the substituted-cysteine accessibility method, but not for A40C and A41C substitutions, which were not found to reside in the open pore. These results indicate that metal ions access the cysteine side chains through the open pore and that closure of the loop gate involves movement of the TM1/E1 region that results in local narrowing of the large aqueous connexin pore.
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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.