ArticleThe Journal of physiology2009
Voltage-dependent and -independent titration of specific residues accounts for complex gating of a ClC chloride channel by extracellular protons.
Article in The Journal of physiology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
39 citing papers in PubMed, 68 citations in OpenAlex.
- pH-mediated activation of the lysosomal arginine sensor SLC38A9.FEBS letters · 2026Article
- pH-dependent regulation in SLC38A9.bioRxiv : the preprint server for biology · 2025Article
- Insights into CLC-0's Slow-Gating from Intracellular Proton Inhibition.International journal of molecular sciences · 2024Article
- Article
- Biophysical and Pharmacological Insights to CLC Chloride Channels.Handbook of experimental pharmacology · 2024Article
- CryoEM structures of the human CLC-2 voltage gated chloride channel reveal a ball and chain gating mechanism.bioRxiv : the preprint server for biology · 2023Article
- Computational Investigation of Mechanisms for pH Modulation of Human Chloride Channels.Molecules (Basel, Switzerland) · 2023Article
- Cryo-EM structures of ClC-2 chloride channel reveal the blocking mechanism of its specific inhibitor AK-42.Nature communications · 2023Article
- Small Molecules Targeting Kidney ClC-K Chloride Channels: Applications in Rare Tubulopathies and Common Cardiovascular Diseases.Biomolecules · 2023Review
- Electro-steric opening of the CLC-2 chloride channel gate.Scientific reports · 2021Article
- Development and validation of a potent and specific inhibitor for the CLC-2 chloride channel.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Article
- Divergent CleLife · 2020Article
- Dynamical model of the CLC-2 ion channel reveals conformational changes associated with selectivity-filter gating.PLoS computational biology · 2020Article
- Chloride Channels in Astrocytes: Structure, Roles in Brain Homeostasis and Implications in Disease.International journal of molecular sciences · 2019Review
- Structure of the CLC-1 chloride channel fromeLife · 2018Article
- Research and progress on ClC‑2 (Review).Molecular medicine reports · 2017Review
- Extracellular protons enable activation of the calcium-dependent chloride channel TMEM16A.The Journal of physiology · 2017Article
- Gating the glutamate gate of CLC-2 chloride channel by pore occupancy.The Journal of general physiology · 2016Article
- Structure and gating of CLC channels and exchangers.The Journal of physiology · 2015Review
Corrections and comments
- Commented on by
Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The ClC transport protein family comprises both Cl(-) ion channel and H(+)/Cl(-) and H(+)/NO(3)(-) exchanger members. Structural studies on a bacterial ClC transporter reveal a pore obstructed at its external opening by a glutamate side-chain which acts as a gate for Cl(-) passage and in addition serves as a staging post for H(+) exchange. This same conserved glutamate acts as a gate to regulate Cl(-) flow in ClC channels. The activity of ClC-2, a genuine Cl(-) channel, has a biphasic response to extracellular pH with activation by moderate acidification followed by abrupt channel closure at pH values lower than approximately 7. We have now investigated the molecular basis of this complex gating behaviour. First, we identify a sensor that couples extracellular acidification to complete closure of the channel. This is extracellularly-facing histidine 532 at the N-terminus of transmembrane helix Q whose neutralisation leads to channel closure in a cooperative manner. We go on to show that acidification-dependent activation of ClC-2 is voltage dependent and probably mediated by protonation of pore gate glutamate 207. Intracellular Cl(-) acts as a voltage-independent modulator, as though regulating the pK(a) of the protonatable residue. Our results suggest that voltage dependence of ClC-2 is given by hyperpolarisation-dependent penetration of protons from the extracellular side to neutralise the glutamate gate deep within the channel, which allows Cl(-) efflux. This is reminiscent of a partial exchanger cycle, suggesting that the ClC-2 channel evolved from its transporter counterparts.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
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.