ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2011
Extracellular spermine exacerbates ischemic neuronal injury through sensitization of ASIC1a channels to extracellular acidosis.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 93 papers.
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Who cites it
93 citing papers in PubMed, 150 citations in OpenAlex.
- Plasma Polyamines and Short-Term Adverse Outcomes Among Patients With Ischemic Stroke: A Prospective Cohort Study.Journal of the American Heart Association · 2024Trial
- Acid-sensing ion channels in ischemic stroke: amplifying and constraining neuronal injury in a phase-specific framework.Pflugers Archiv : European journal of physiology · 2026Review
- The multifaceted role of ASICs channels into the nervous system and their potential use as a therapeutic target for neuro-disorders.Journal of neural transmission (Vienna, Austria : 1996) · 2026Review
- Untargeted red blood cell metabolomics reveals distinct metabolic signatures in malignant cerebral edema following acute ischemic stroke.BMC neurology · 2026Article
- Article
- Age-Dependent Redistribution of the Life-Important Enzyme in the Retina: Adult Müller Glial Cells' Endfeet Lack Spermine Synthase Expression.Biomolecules · 2025Article
- Combining Metabolomics and Proteomics to Reveal Key Serum Compounds Related to Canine Intervertebral Disc Herniation.Metabolites · 2025Article
- PFKM-Mediated Glycolysis: A Pathway for ASIC1 to Enhance Cell Survival in the Acidic Microenvironment of Liver Cancer.Biomolecules · 2025Article
- Astrocytic Acid-Sensing Ion Channel 1a Contributes to the Development of Epileptic Cognitive Impairment.Biomolecules · 2025Article
- Voltage-clamp fluorometry for advancing mechanistic understanding of ion channel mechanisms with a focus on acid-sensing ion channels.Biochemical Society transactions · 2024Review
- Identification of SLC45A4 as a pain gene encoding a neuronal polyamine transporter.bioRxiv : the preprint server for biology · 2024Article
- Cholestane-3β,5α,6β-Triol Inhibits Acid-Sensing Ion Channels and Reduces Acidosis-Mediated Ischemic Brain Injury.Stroke · 2024Article
- Hi1a Improves Sensorimotor Deficit following Endothelin-1-Induced Stroke in Rats but Does Not Improve Functional Outcomes following Filament-Induced Stroke in Mice.ACS pharmacology & translational science · 2024Article
- 4-(Azolyl)-Benzamidines as a Novel Chemotype for ASIC1a Inhibitors.International journal of molecular sciences · 2024Article
- Molecular determinants of ASIC1 modulation by divalent cations.Scientific reports · 2024Article
- Opioid Analgesic as a Positive Allosteric Modulator of Acid-Sensing Ion Channels.International journal of molecular sciences · 2024Article
- Proton-sensing ion channels, GPCRs and calcium signaling regulated by them: implications for cancer.Frontiers in cell and developmental biology · 2024Review
- Possible Compensatory Role of ASICs in Glutamatergic Synapses.International journal of molecular sciences · 2023Article
- Anxiolytic, Analgesic and Anti-Inflammatory Effects of Peptides Hmg 1b-2 and Hmg 1b-4 from the Sea AnemoneToxins · 2023Article
- Triggering of Major Brain Disorders by Protons and ATP: The Role of ASICs and P2X Receptors.Neuroscience bulletin · 2023Review
33 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 5 institutions in 2 countries.
Funding
Abstract
Ischemic brain injury is a major problem associated with stroke. It has been increasingly recognized that acid-sensing ion channels (ASICs) contribute significantly to ischemic neuronal damage, but the underlying mechanism has remained elusive. Here, we show that extracellular spermine, one of the endogenous polyamines, exacerbates ischemic neuronal injury through sensitization of ASIC1a channels to extracellular acidosis. Pharmacological blockade of ASIC1a or deletion of the ASIC1 gene greatly reduces the enhancing effect of spermine in ischemic neuronal damage both in cultures of dissociated neurons and in a mouse model of focal ischemia. Mechanistically, spermine profoundly reduces desensitization of ASIC1a by slowing down desensitization in the open state, shifting steady-state desensitization to more acidic pH, and accelerating recovery between repeated periods of acid stimulation. Spermine-mediated potentiation of ASIC1a activity is occluded by PcTX1 (psalmotoxin 1), a specific ASIC1a inhibitor binding to its extracellular domain. Functionally, the enhanced channel activity is accompanied by increased acid-induced neuronal membrane depolarization and cytoplasmic Ca(2+) overload, which may partially explain the exacerbated neuronal damage caused by spermine. More importantly, blocking endogenous spermine synthesis significantly attenuates ischemic brain injury mediated by ASIC1a but not that by NMDA receptors. Thus, extracellular spermine contributes significantly to ischemic neuronal injury through enhancing ASIC1a activity. Our data suggest new neuroprotective strategies for stroke patients via inhibition of polyamine synthesis and subsequent spermine-ASIC interaction.
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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.