ArticleProceedings of the National Academy of Sciences of the United States of America2022
Molecular determinants of pH sensing in the proton-activated chloride channel.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 33 citations in OpenAlex.
- Conformational Fingerprints Underlying Thermal Modulation of PAC/TMEM206 Gating.International journal of molecular sciences · 2026Article
- Proton-activated chloride channel 1 is essential for innate host defense against bacterial sepsis.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- PAC regulates endo-, and exocytosis, and lysosomal-mitochondrial stress signaling in human mast cells.Cell communication and signaling : CCS · 2026Article
- TMEM206 gene knockout improves balance performance in SCA1 transgenic mice.IBRO neuroscience reports · 2025Article
- Cells adapt to extracellular acidic pH through TM9SF3-mediated PI(4,5)PNature communications · 2025Article
- Article
- Assessing the Causal Relationships Between Lipid Species and Stroke by Using Mendelian Randomization.Molecular neurobiology · 2025Article
- The function of chloride channels in digestive system disease (Review).International journal of molecular medicine · 2025Review
- Loss of the proton-activated chloride channel in neurons impairs AMPA receptor endocytosis and LTD via endosomal hyper-acidification.Cell reports · 2025Article
- Alternative splicing regulates PACC1 function and promotes acidosis-induced cytotoxicity.Frontiers in cell and developmental biology · 2025Article
- The ion channels of endomembranes.Physiological reviews · 2024Review
- Chloride Homeostasis Regulates cGAS-STING Signaling.bioRxiv : the preprint server for biology · 2024Article
- Bicarbonate signalling via G protein-coupled receptor regulates ischaemia-reperfusion injury.Nature communications · 2024Article
- Physiological Functions of the Volume-Regulated Anion Channel VRAC/LRRC8 and the Proton-Activated Chloride Channel ASOR/TMEM206.Handbook of experimental pharmacology · 2024Article
- A new polymodal gating model of the proton-activated chloride channel.PLoS biology · 2023Article
- Article
- Molecular mechanism underlying desensitization of the proton-activated chloride channel PAC.eLife · 2022Article
- Constant pH molecular dynamics simulations: Current status and recent applications.Current opinion in structural biology · 2022Review
- Review
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
Abstract
In response to acidic pH, the widely expressed proton-activated chloride (PAC) channel opens and conducts anions across cellular membranes. By doing so, PAC plays an important role in both cellular physiology (endosome acidification) and diseases associated with tissue acidosis (acid-induced cell death). Despite the available structural information, how proton binding in the extracellular domain (ECD) leads to PAC channel opening remains largely unknown. Here, through comprehensive mutagenesis and electrophysiological studies, we identified several critical titratable residues, including two histidine residues (H130 and H131) and an aspartic acid residue (D269) at the distal end of the ECD, together with the previously characterized H98 at the transmembrane domain-ECD interface, as potential pH sensors for human PAC. Mutations of these residues resulted in significant changes in pH sensitivity. Some combined mutants also exhibited large basal PAC channel activities at neutral pH. By combining molecular dynamics simulations with structural and functional analysis, we further found that the β12 strand at the intersubunit interface and the associated "joint region" connecting the upper and lower ECDs allosterically regulate the proton-dependent PAC activation. Our studies suggest a distinct pH-sensing and gating mechanism of this new family of ion channels sensitive to acidic environment.
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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.