ArticleeLife2022
Conformational decoupling in acid-sensing ion channels uncovers mechanism and stoichiometry of PcTx1-mediated inhibition.
Article in eLife, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 14 citations in OpenAlex.
- Conformational plasticity of human acid-sensing ion channel 1a.Nature structural & molecular biology · 2026Article
- Scorpion Venom Peptides: From Structural Scaffolds to Therapeutic Applications-A Focus on Antioxidant Mechanisms and Translational Perspectives.Antioxidants (Basel, Switzerland) · 2026Review
- Identification, characterization, and structure-activity relationship of the ASIC3-selective peptide WRPRFa.Communications chemistry · 2025Article
- The Role of miRNAs in the Differential Diagnosis of Alzheimer's Disease and Major Depression: A Bioinformatics-Based Approach.International journal of molecular sciences · 2025Article
- Mechanism of acid-sensing ion channel modulation by Hi1a.The Journal of general physiology · 2024Article
- Proline substitutions in the ASIC1 β11-12 linker slow desensitization.Biophysical journal · 2024Article
- Mutagenesis of the Peptide Inhibitor of ASIC3 Channel Introduces Binding to Thumb Domain of ASIC1a but Reduces Analgesic Activity.Marine drugs · 2024Article
- Dynamic conformational changes of acid-sensing ion channels in different desensitizing conditions.Biophysical journal · 2024Article
- Revealing molecular determinants governing mambalgin-3 pharmacology at acid-sensing ion channel 1 variants.Cellular and molecular life sciences : CMLS · 2024Article
- Proline substitutions in the ASIC1 β11-12 linker slow desensitization.bioRxiv : the preprint server for biology · 2024Article
- Can pyroptosis be a new target in rheumatoid arthritis treatment?Frontiers in immunology · 2023Review
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Acid-sensing ion channels (ASICs) are trimeric proton-gated cation channels involved in fast synaptic transmission. Pharmacological inhibition of ASIC1a reduces neurotoxicity and stroke infarct volumes, with the cysteine knot toxin psalmotoxin-1 (PcTx1) being one of the most potent and selective inhibitors. PcTx1 binds at the subunit interface in the extracellular domain (ECD), but the mechanism and conformational consequences of the interaction, as well as the number of toxin molecules required for inhibition, remain unknown. Here, we use voltage-clamp fluorometry and subunit concatenation to decipher the mechanism and stoichiometry of PcTx1 inhibition of ASIC1a. Besides the known inhibitory binding mode, we propose PcTx1 to have at least two additional binding modes that are decoupled from the pore. One of these modes induces a long-lived ECD conformation that reduces the activity of an endogenous neuropeptide. This long-lived conformational state is proton-dependent and can be destabilized by a mutation that decreases PcTx1 sensitivity. Lastly, the use of concatemeric channel constructs reveals that disruption of a single PcTx1 binding site is sufficient to destabilize the toxin-induced conformation, while functional inhibition is not impaired until two or more binding sites are mutated. Together, our work provides insight into the mechanism of PcTx1 inhibition of ASICs and uncovers a prolonged conformational change with possible pharmacological implications.
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