ArticleThe Journal of biological chemistry2011
Nonproton ligand sensing domain is required for paradoxical stimulation of acid-sensing ion channel 3 (ASIC3) channels by amiloride.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 50 citations in OpenAlex.
- Epithelial NaComprehensive Physiology · 2024Review
- Function and phylogeny support the independent evolution of an ASIC-like Deg/ENaC channel in the Placozoa.Communications biology · 2023Article
- The diverse functions of the DEG/ENaC family: linking genetic and physiological insights.The Journal of physiology · 2023Article
- Physiological insight into the conserved properties of Caenorhabditis elegans acid-sensing degenerin/epithelial sodium channels.The Journal of physiology · 2023Article
- Distinct roles for twoeLife · 2022Article
- Acid-sensing ion channel 3: An analgesic target.Channels (Austin, Tex.) · 2021Review
- Citric Acid in Drug Formulations Causes Pain by Potentiating Acid-Sensing Ion Channel 1.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2021Article
- Paradoxical Potentiation of Acid-Sensing Ion Channel 3 (ASIC3) by AmilorideFrontiers in physiology · 2021Article
- A NaThe Journal of biological chemistry · 2019Article
- Hydrophobic Amines and Their Guanidine Analogues Modulate Activation and Desensitization of ASIC3.International journal of molecular sciences · 2019Article
- Subtype-selective inhibition of acid-sensing ion channel 3 by a natural flavonoid.CNS neuroscience & therapeutics · 2019Article
- Potentiation and Block of ASIC1a by Memantine.Cellular and molecular neurobiology · 2018Article
- Proton-independent activation of acid-sensing ion channel 3 by an alkaloid, lindoldhamine, from Laurus nobilis.British journal of pharmacology · 2018Article
- Acidotoxicity via ASIC1a Mediates Cell Death during Oxygen Glucose Deprivation and Abolishes Excitotoxicity.ACS chemical neuroscience · 2017Article
- Properties of acid-induced currents in mouse dorsal root ganglia neurons.Physiological reports · 2016Article
- Ischemic postconditioning protects against ischemic brain injury by up-regulation of acid-sensing ion channel 2a.Neural regeneration research · 2016Article
- Non-acidic activation of pain-related Acid-Sensing Ion Channel 3 by lipids.The EMBO journal · 2016Article
- Article
- Protons and Psalmotoxin-1 reveal nonproton ligand stimulatory sites in chicken acid-sensing ion channel: Implication for simultaneous modulation in ASICs.Channels (Austin, Tex.) · 2014Article
- Acid-sensing ion channels (ASICs): therapeutic targets for neurological diseases and their regulation.BMB reports · 2013Review
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Acid-sensing ion channels (ASICs), which belong to the epithelial sodium channel/degenerin family, are activated by extracellular protons and are inhibited by amiloride (AMI), an important pharmacological tool for studying all known members of epithelial sodium channel/degenerin. In this study, we reported that AMI paradoxically opened homomeric ASIC3 and heteromeric ASIC3 plus ASIC1b channels at neutral pH and synergistically enhanced channel activation induced by mild acidosis (pH 7.2 to 6.8). The characteristic profile of AMI stimulation of ASIC3 channels was reminiscent of the channel activation by the newly identified nonproton ligand, 2-guanidine-4-methylquinazoline. Using site-directed mutagenesis, we showed that ASIC3 activation by AMI, but not its inhibitory effect, was dependent on the integrity of the nonproton ligand sensing domain in ASIC3 channels. Moreover, the structure-activity relationship study demonstrated the differential requirement of the 5-amino group in AMI for the stimulation or inhibition effect, strengthening the different interactions within ASIC3 channels that confer the paradoxical actions of AMI. Furthermore, using covalent modification analyses, we provided strong evidence supporting the nonproton ligand sensing domain is required for the stimulation of ASIC3 channels by AMI. Finally, we showed that AMI causes pain-related behaviors in an ASIC3-dependent manner. These data reinforce the idea that ASICs can sense nonproton ligands in addition to protons. The results also indicate caution in the use of AMI for studying ASIC physiology and in the development of AMI-derived ASIC inhibitors for treating pain syndromes.
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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.