Acid-sensing Ion Channel 1a Research Articles

Nonselective Cation Channels Maintain Alveolar Fluid Clearance After Exposure to Toxins from Respiratory Pathogens

Normal gas exchange in the alveoli is facilitated by a thin fluid layer. This layer is carefully regulated by two ion channels: highly selective channels (HSC or ENaC) and nonselective cation channels (NSC). Previous research found that both channels contribute about equally to alveolar fluid clearance (AFC). Since the molecular composition of NSC is a recent discovery, not much is known about NSC’s response to various respiratory pathogens. NSC are composed of an alpha‐ENaC subunit and at least one acid‐sensing ion channel 1a (ASIC1a) subunit. Our study aims are to understand how NSC contribute to alveolar epithelial permeability and how the lungs respond to toxins from respiratory pathogens. We hypothesize that AFC will be lower in the absence of ASIC1a (ASIC1 KO) when exposed to toxins from respiratory pathogens: Lipopolysaccharide (LPS) from E. coli and Pneumolysin (PLY) from P. pneumoniae. Additionally, we hypothesize that ASIC1 KO animals will have increased baseline alveolar epithelium permeability. All animal experiments were approved by Emory’s IACUC.We introduced pathogen toxins via intratracheal instillation to ASIC1 KO (KO) and wildtype (WT) mouse models (both on a C57Bl6 background). After a four‐hour incubation period, we euthanized the mice by isoflurane overdose. We determined AFC by instilling their lungs with 0.7ml of a 2.0% Evans Blue (EB) or Fluorescein isothiocyanate–dextran (FITC) solution via the trachea. We took samples at t=0 and t=30 minutes after instillation. We determined the EB/ FITC concentration of both samples using spectrophotometry and calculated AFC from the change in dye concentration.Our preliminary findings suggest that LPS and PLY inhibit all AFC associated with HSC leaving only AFC associated with NSC. The AFC of LPS exposed KO animals is low compared to AFC for LPS exposed WT animals (6.04 ± 3.02, n= 15 vs 15.8 ± 5.61, n= 11, p< 0.001). Similarly, AFC of PLY exposed KO mice is lower than AFC for PLY exposed WT mice (2.78 ± 0.96, n= 10 vs 12.4 ± 4.36, n= 4, p< 0.001). In the toxin exposed KO groups, neither HSC nor NSC are fully functioning or contributing to AFC. We are still collecting data on the permeability of the alveolar epithelium.There is evidence to suggest that the regulation of HSC and NSC are drastically different. Given the critical nature of the alveoli fluid layer, it would be logical that NSC channels serve as a compensatory mechanism when HSC are inhibited by pathogens. These findings can help guide treatment for alveolar flooding caused by toxins from different respiratory pathogens.

ASIC1a stimulates the resistance of human hepatocellular carcinoma by promoting EMT via the AKT/GSK3β/Snail pathway driven by TGFβ/Smad signals.

Multidrug resistance is the main obstacle to curing hepatocellular carcinoma (HCC). Acid‐sensing ion channel 1a (ASIC1a) has critical roles in all stages of cancer progression, especially invasion and metastasis, and in resistance to therapy. Epithelial to mesenchymal transition (EMT) transforms epithelial cells into mesenchymal cells after being stimulated by extracellular factors and is closely related to tumour infiltration and resistance. We used Western blotting, immunofluorescence, qRT‐PCR, immunohistochemical staining, MTT, colony formation and scratch healing assay to determine ASIC1a levels and its relationship to cell proliferation, migration and invasion. ASIC1a is overexpressed in HCC tissues, and the amount increased in resistant HCC cells. EMT occurred more frequently in drug‐resistant cells than in parental cells. Inactivation of ASIC1a inhibited cell migration and invasion and increased the chemosensitivity of cells through EMT. Overexpression of ASIC1a upregulated EMT and increased the cells’ proliferation, migration and invasion and induced drug resistance; knocking down ASIC1a with shRNA had the opposite effects. ASIC1a increased cell migration and invasion through EMT by regulating α and β‐catenin, vimentin and fibronectin expression via the AKT/GSK‐3β/Snail pathway driven by TGFβ/Smad signals. ASIC1a mediates drug resistance of HCC through EMT via the AKT/GSK‐3β/Snail pathway.

Pharmacological Validation of ASIC1a as a Druggable Target for Neuroprotection in Cerebral Ischemia Using an Intravenously Available Small Molecule Inhibitor.

Acidosis is a hallmark of ischemic stroke and a promising neuroprotective target for preventing neuronal injury. Previously, genetic manipulations showed that blockade of acid-sensing ion channel 1a (ASIC1a)-mediated acidotoxicity could dramatically alleviate the volume of brain infarct and restore neurological function after cerebral ischemia. However, few pharmacological candidates have been identified to exhibit efficacy on ischemic stroke through inhibition of ASIC1a. In this work, we examined the ability of a toxin-inspired compound 5b (C5b), previously found to effectively inhibit ASIC1a in vitro, to exert protective effects in animal models of ischemic stroke in vivo. We found that C5b exerts significant neuroprotective effects not only in acid-induced neuronal death in vitro but also ischemic brain injury in vivo, suggesting that ASIC1a is a druggable target for therapeutic development. More importantly, C5b is able to cross the blood brain barrier and significantly reduce brain infarct volume when administered intravenously in the ischemic animal model, highlighting its systemic availability for therapies against neurodegeneration due to acidotoxicity. Together, our data demonstrate that C5b is a promising lead compound for neuroprotection through inhibiting ASIC1a, which warrants further translational studies.

Acid-sensing ion channel 1a regulates the specificity of reconsolidation of conditioned threat responses.

Recent research on altering threat memory has focused on a reconsolidation window. During reconsolidation, threat memories are retrieved and become labile. Reconsolidation of distinct threat memories is synapse dependent, whereas the underlying regulatory mechanism of the specificity of reconsolidation is poorly understood. We designed a unique behavioral paradigm in which a distinct threat memory can be retrieved through the associated conditioned stimulus. In addition, we proposed a regulatory mechanism by which the activation of acid-sensing ion channels (ASICs) strengthens the distinct memory trace associated with the memory reconsolidation to determine its specificity. The activation of ASICs by CO2 inhalation, when paired with memory retrieval, triggers the reactivation of the distinct memory trace, resulting in greater memory lability. ASICs potentiate the memory trace by altering the amygdala-dependent synaptic transmission and plasticity at selectively targeted synapses. Our results suggest that inhaling CO2 during the retrieval event increases the lability of a threat memory through a synapse-specific reconsolidation process.

Correction to "The Intracellular N-Terminal Domain of the Acid-Sensing Ion Channel 1a Participates in Channel Opening and Membrane Expression".

In the above article [Li W, Wang X, Meng X, and Wei D (2021) Mol Pharmacol 100: [113-118][1]; DOI: <https://doi.org/10.1124/molpharm.120.000153>], an author name was inadvertently omitted. The correct authors of the article are Wen Li, Xiaomu Wang, Xiandong Meng, Wen Jiang, and Dong Wei. In

The Role of ASIC1a in Epilepsy: A Potential Therapeutic Target.

Background Epilepsy represents one of the most common brain diseases among humans. Tissue acidosis is a common phenomenon in epileptogenic foci. Moreover, its role in epileptogenesis remains unclear. Acid-sensing ion channel-1a (ASIC1a) represents a potential way to assess new therapies. ASIC1a, mainly expressed in the mammalian brain, is a type of protein-gated cation channel. It has been shown to play an important role in the pathological mechanism of various diseases, including stroke, epilepsy, and multiple sclerosis.Methods Data were collected from Web of Science, Medline, PubMed, through searching for these keywords: “Acid-sensing ion channels 1a” or “ASIC1a” and “epilepsy” or “seizure”.Results The role of ASIC1a in epilepsy remains controversial; it may represent a promising therapeutic target of epilepsy.Conclusion This review is intended to provide an overview of the structure, trafficking, and molecular mechanisms of ASIC1a in order to elucidate the role of ASIC1a in epilepsy further.

Post-acquisition CO2 Inhalation Enhances Fear Memory and Depends on ASIC1A.

A growing body of evidence suggests that memories of fearful events may be altered after initial acquisition or learning. Although much of this work has been done in rodents using Pavlovian fear conditioning, it may have important implications for fear memories in humans such as in post-traumatic stress disorder (PTSD). A recent study suggested that cued fear memories, made labile by memory retrieval, were made additionally labile and thus more vulnerable to subsequent modification when mice inhaled 10% carbon dioxide (CO2) during retrieval. In light of this finding, we hypothesized that 10% CO2 inhalation soon after fear acquisition might affect memory recall 24 h later. We found that both cue and context fear memory were increased by CO2 exposure after fear acquisition. The effect of CO2 was time-dependent, as CO2 inhalation administered 1 or 4 h after cued fear acquisition increased fear memory, whereas CO2 inhalation 4 h before or 24 h after cued fear acquisition did not increase fear memory. The ability of CO2 exposure following acquisition to enhance fear memory was not a general consequence of stress, as restraining mice after acquisition did not alter cued fear memory. The memory-enhancing action of CO2 may be relatively specific to fear conditioning as novel object recognition was impaired by post-training CO2 inhalation. To explore the molecular underpinnings of these effects, we tested if they depended on the acid-sensing ion channel-1a (ASIC1A), a proton-gated cation channel that mediates other effects of CO2, likely via its ability to sense acidosis induced during CO2 inhalation. We found that CO2 inhalation did not alter cued or context fear memory in Asic1a–/– mice, suggesting that this phenomenon critically depends on ASIC1A. These results suggest that brain acidosis around the time of a traumatic event may enhance memory of the trauma, and may thus constitute an important risk factor for developing PTSD. Moreover, preventing peritraumatic acidosis might reduce risk of PTSD.

Total Synthesis of the Spider-Venom Peptide Hi1a.

Hi1a is a venom peptide from the Australian funnel-web spider Hadronyche infensa with a complex tertiary structure. Hi1a has neuroprotective and cardioprotective properties due to its potent inhibition of acid-sensing ion channel 1a (ASIC1a) and is currently being pursued as a novel therapy for acute ischemic events. Herein, we describe the total synthesis of Hi1a using native chemical ligation. The synthetic peptide was successfully folded and exhibited similar inhibitory activity on ASIC1a to recombinant Hi1a.

Correction to: Therapeutic Inhibition of Acid Sensing Ion Channel 1a Recovers Heart Function After Ischemia-Reperfusion Injury.

Correction to: Therapeutic Inhibition of Acid Sensing Ion Channel 1a Recovers Heart Function After Ischemia-Reperfusion Injury.

Regulation of gliomagenesis and stemness through acid sensor ASIC1a.

Glioblastoma multiforme (GBM) is the most prevalent and aggressive type of adult gliomas. Despite intensive therapy including surgery, radiation, and chemotherapy, invariable tumor recurrence occurs, which suggests that glioblastoma stem cells (GSCs) render these tumors persistent. Recently, the induction of GSC differentiation has emerged as an alternative method to treat GBM, and most of the current studies aim to convert GSCs to neurons by a combination of transcriptional factors. As the tumor microenvironment is typically acidic due to increased glycolysis and consequently leads to an increased production of lactic acid in tumor cells, in the present study, the role of acid-sensing ion channel 1a (ASIC1a), an acid sensor, was explored as a tumor suppressor in gliomagenesis and stemness. The bioinformatics data from The Cancer Genome Atlas revealed that ASIC1 expression levels in GBM tumor tissues were lower than those in normal brain, and glioma patients with high ASIC1 expression had longer survival than those with low ASIC1 expression. Our immunohistochemistry data from tissue microarray revealed that ASIC1a expression was negatively associated with glioma grading. Functional studies revealed that the downregulation of ASIC1a promoted glioma cell proliferation and invasion, while upregulation of ASIC1a inhibited their proliferation and invasion. Furthermore, ASIC1a suppressed growth and proliferation of glioma cells through G1/S arrest and apoptosis induction. Mechanistically, ASIC1a negatively modulated glioma stemness via inhibition of the Notch signaling pathway and GSC markers CD133 and aldehyde dehydrogenase 1. ASIC1a is a tumor suppressor in gliomagenesis and stemness and may serve as a promising prognostic biomarker and target for GBM patients.

High-throughput characterization of photocrosslinker-bearing ion channel variants to map residues critical for function and pharmacology.

Incorporation of noncanonical amino acids (ncAAs) can endow proteins with novel functionalities, such as crosslinking or fluorescence. In ion channels, the function of these variants can be studied with great precision using standard electrophysiology, but this approach is typically labor intensive and low throughput. Here, we establish a high-throughput protocol to conduct functional and pharmacological investigations of ncAA-containing human acid-sensing ion channel 1a (hASIC1a) variants in transiently transfected mammalian cells. We introduce 3 different photocrosslinking ncAAs into 103 positions and assess the function of the resulting 309 variants with automated patch clamp (APC). We demonstrate that the approach is efficient and versatile, as it is amenable to assessing even complex pharmacological modulation by peptides. The data show that the acidic pocket is a major determinant for current decay, and live-cell crosslinking provides insight into the hASIC1a-psalmotoxin 1 (PcTx1) interaction. Further, we provide evidence that the protocol can be applied to other ion channels, such as P2X2 and GluA2 receptors. We therefore anticipate the approach to enable future APC-based studies of ncAA-containing ion channels in mammalian cells.

Dynorphin Neuropeptides Decrease Apparent Proton Affinity of ASIC1a by Occluding the Acidic Pocket.

Prolonged acidosis, as it occurs during ischemic stroke, induces neuronal death via acid-sensing ion channel 1a (ASIC1a). Concomitantly, it desensitizes ASIC1a, highlighting the pathophysiological significance of modulators of ASIC1a acid sensitivity. One such modulator is the opioid neuropeptide big dynorphin (Big Dyn) which binds to ASIC1a and enhances its activity during prolonged acidosis. The molecular determinants and dynamics of this interaction remain unclear, however. Here, we present a molecular interaction model showing a dynorphin peptide inserting deep into the acidic pocket of ASIC1a. We confirmed experimentally that the interaction is predominantly driven by electrostatic forces, and using noncanonical amino acids as photo-cross-linkers, we identified 16 residues in ASIC1a contributing to Big Dyn binding. Covalently tethering Big Dyn to its ASIC1a binding site dramatically decreased the proton sensitivity of channel activation, suggesting that Big Dyn stabilizes a resting conformation of ASIC1a and dissociates from its binding site during channel opening.

A role for substance P and acid-sensing ion channel 1a in prolotherapy with dextrose-mediated analgesia in a mouse model of chronic muscle pain.

Prolotherapy is widely used in pain control and tissue repair in pain medicine. The classical mode is injection with hypertonic dextrose in muscle or perimysium. However, the analgesic mechanism is still not known. Here, we successfully established dextrose-mediated antinociception in a mouse model of fibromyalgia. The antinociceptive effects of dextrose injections were evaluated in a mouse model of fibromyalgia, in which bilateral chronic mechanical hyperalgesia was induced by unilateral intramuscular acid injection. The injectant (dextrose), dose (≥5%), and volume (>10 μL), but not osmolarity, were essential for the prolotherapy. Further studies showed that the activation of acid-sensing ion channel 1a (ASIC1a), neural activation, and the release of substance P from muscle afferents were required in the dextrose-induced reduction of mechanical hypersensitivity. Both pharmacological blockade and genetic deletion of ASIC1a or substance P as well as lidocaine abolished the dextrose-induced antinociception in mice with chronic hyperalgesia. Moreover, intramuscular dextrose injection induced phosphorylated extracellular signal-regulated kinase expression in dorsal root ganglion neurons expressing substance P; the phosphorylated extracellular signal-regulated kinase expression was inhibited by the ASIC1a antagonist PcTx1. The optimal settings for prolotherapy in fibromyalgia-like pain are dextrose dependent and volume dependent, and the peripheral antinociception involves ASIC1a and substance P signaling in muscle afferents. This study suggests a possible mechanism of action of dextrose prolotherapy in noninflammatory muscle pain such as fibromyalgia and provides insights into treating other types of chronic pain.

Commentary: Slowing of the Time Course of Acidification Decreases the Acid-Sensing Ion Channel 1a Current Amplitude and Modulates Action Potential Firing in Neurons.

Commentary: Slowing of the Time Course of Acidification Decreases the Acid-Sensing Ion Channel 1a Current Amplitude and Modulates Action Potential Firing in Neurons.

Therapeutic Inhibition of Acid-Sensing Ion Channel 1a Recovers Heart Function After Ischemia-Reperfusion Injury.

Ischemia-reperfusion injury (IRI) is one of the major risk factors implicated in morbidity and mortality associated with cardiovascular disease. During cardiac ischemia, the buildup of acidic metabolites results in decreased intracellular and extracellular pH, which can reach as low as 6.0 to 6.5. The resulting tissue acidosis exacerbates ischemic injury and significantly affects cardiac function. We used genetic and pharmacologic methods to investigate the role of acid-sensing ion channel 1a (ASIC1a) in cardiac IRI at the cellular and whole-organ level. Human induced pluripotent stem cell-derived cardiomyocytes as well as ex vivo and in vivo models of IRI were used to test the efficacy of ASIC1a inhibitors as pre- and postconditioning therapeutic agents. Analysis of human complex trait genetics indicates that variants in the ASIC1 genetic locus are significantly associated with cardiac and cerebrovascular ischemic injuries. Using human induced pluripotent stem cell-derived cardiomyocytes in vitro and murine ex vivo heart models, we demonstrate that genetic ablation of ASIC1a improves cardiomyocyte viability after acute IRI. Therapeutic blockade of ASIC1a using specific and potent pharmacologic inhibitors recapitulates this cardioprotective effect. We used an in vivo model of myocardial infarction and 2 models of ex vivo donor heart procurement and storage as clinical models to show that ASIC1a inhibition improves post-IRI cardiac viability. Use of ASIC1a inhibitors as preconditioning or postconditioning agents provided equivalent cardioprotection to benchmark drugs, including the sodium-hydrogen exchange inhibitor zoniporide. At the cellular and whole organ level, we show that acute exposure to ASIC1a inhibitors has no effect on cardiac ion channels regulating baseline electromechanical coupling and physiologic performance. Our data provide compelling evidence for a novel pharmacologic strategy involving ASIC1a blockade as a cardioprotective therapy to improve the viability of hearts subjected to IRI.

OTME-19. Regula Regulation of Gliomagenesis and Stemness Through Acid Sensor ASIC1a

Glioblastoma multiforme (GBM) is the most prevalent and aggressive type of adult gliomas. Despite intensive therapy including surgery, radiation, and chemotherapy, invariable tumor recurrence occurs, which suggests that glioblastoma stem cells (GSC) render these tumors persistent. Recently, GSC differentiation has emerged as an alternative method to treat GBM, and most of current studies aim to convert GSC to neurons by a combination of transcriptional factors. As the tumor microenvironment is typically acidic due to increased glycolysis in tumor cells, here, we explored the role of acid-sensing ion channel 1a (ASIC1a), an acid sensor, as a tumor suppressor in gliomagenesis and stemness. The bioinformatics data from TCGA shows that ASIC1 expression levels in GBM tumor tissues were lower than those in normal brain, and glioma patients with elevated ASIC1 expression have longer survival than those with lowered ASIC1 expression. Our immunohistochemistry data from tissue microarray shows that ASIC1a expression is negatively correlated with glioma grading. Functional studies reveal that the downregulation of ASIC1a promotes glioma cell proliferation and invasion, while upregulation of ASIC1a inhibits their proliferation and invasion. Furthermore, ASIC1a suppresses glioma cells’ growth and proliferation through G1/S arrest and apoptosis induction. Mechanistically, ASIC1a negatively modulates glioma stemness via inhibition of the Notch signaling pathway and GSC markers CD133 and ALDH1. Our findings indicate that ASIC1a is a tumor suppressor in gliomagenesis and stemness and may serve as a promising prognostic biomarker and target for GBM patients.

ASIC1a promotes acidic microenvironment-induced HCC cells migration and invasion by inducing autophagy

Hepatocellular carcinoma (HCC) is one of the most common types of liver cancer with high incidence and metastatic rate. Recent studies have shown that the high metastasis of HCC is closely related to the acidic microenvironment of HCC cells. Acid-sensing ion Channel 1a (ASIC1a) plays an important role in HCC development, which can mediate tumor cell migration and invasion. However, the underlying mechanism of how ASIC1a promotes HCC cell migration and invasion in acidic microenvironments remains unclear, while autophagy may act as a mechanism for tumor cells to adapt to acidic microenvironment. Therefore, this study aims to investigate whether ASIC1a mediates autophagy and its effects on the migration and invasion of HCC cells. Interestingly, our study has shown that ASIC1a and autophagy were increased in HepG2 cells in acidic microenvironment, and both of them can promote HCC cells migration and invasion. Moreover, inhibition of ASIC1a with PcTx1 or ASIC1a ShRNA reduced the autophagy flux. Collectively, ASIC1a can promote acidic microenvironment-induced HepG2 cells migration and invasion by inducing autophagy, which may be correlated with Ca2+ influx.

The Intracellular N-Terminal Domain of the Acid-Sensing Ion Channel 1a Participates in Channel Opening and Membrane Expression.

Acid-sensing ion channels (ASICs) are widely expressed in the nervous system. The intracellular C terminus of ASIC1a has many sites involved in regulating its expression and the opening mechanism, but the role of the intracellular N-terminal domain is poorly understood. Here, we explored the correlation of ASIC1a intracellular N terminus with membrane expression and gate opening. We modified the N-terminal structure of ASICs by deletion/truncation/mutation strategies and transfected the recombinant plasmids into CHO cells. Protein expression was analyzed with immunofluorescence, Western blots, and patch-clamp experiments. Deleting the entire N terminus decreased the membrane expression of channel proteins, and ion channel opening was lost. Deleting sections of the N terminus also decreased membrane expression and suggested that all areas were significant, with no single or group of amino acid residues playing a decisive role in regulating ASIC1a membrane expression. In terms of gate opening, five amino acid (AA) residues from AA 16 to AA 20 participated in gate opening, and isoleucine at AA 18 was the most important. The whole N terminus of ASICs participates in the membrane expression of ASIC1a, and five amino acid residues (AA 16-20) are involved in the gate opening mechanism. SIGNIFICANCE STATEMENT: The whole N terminus of ASICs participates in the membrane expression of ASIC1a, and five amino acid resi-dues (amino acid 16-20) are involved in the gate opening mechanism.

Estrogen Protects Articular Cartilage by Downregulating ASIC1a in Rheumatoid Arthritis.

PurposeThe severity of rheumatoid arthritis (RA) in women is generally lower than that in men. RA is mediated, at least in part, by the protective effects of estradiol. However, the mechanisms underlying the protective effect of estradiol on RA are still unclear. Recent studies have demonstrated that activation of acid-sensing ion channel 1a (ASIC1a) by tissue acidosis plays an important role in the injury of cartilage in RA. Here, we assessed the effects of estradiol on acid-mediated cartilage injury both in vitro and in vivo and explored the involvement of ASIC1a in RA and its underlying mechanism.MethodsCultured primary articular chondrocytes were subjected to acidosis-mediated injury in vitro. Beclin1, LC3, p62, GPER1, and ASIC1a expression was detected through Western blotting, quantitative real-time PCR, and immunofluorescence analysis. Adjuvant arthritis (AA) was induced in rats through intradermal immunization by injecting 0.25 mL heat-killed mycobacteria (10 mg/mL) suspended in complete Freund’s adjuvant into the left hind metatarsal footpad. The levels of estrogen and related inflammatory factors in the serum were measured using enzyme-linked immunosorbent assay. The expression of ASIC1a and autophagy-related proteins was detected through immunohistochemical analysis and Western blot.ResultsTreatment of primary articular chondrocytes with estradiol decreased the expression of ASIC1a and autophagy level. The symptoms of cartilage damage and levels of inflammatory cytokines in the serum were reduced after estradiol treatment in the rats with AA. In addition, estradiol treatment reduced ASIC1a expression via the PI3K-AKT-mTOR pathway, among which G-protein coupled estradiol receptor 1 (GPER1) plays a regulatory role. Finally, the level of autophagy in chondrocytes was decreased by the selective ASIC1a blocker psalmotoxin-1 (PCTX-1).ConclusionEstradiol can protect the cartilage of rats with AA against acidosis-mediated damage and autophagy by suppressing ASIC1a expression through GPER1.

Acid-Sensing Ion Channel-1a in Articular Chondrocytes and Synovial Fibroblasts: A Novel Therapeutic Target for Rheumatoid Arthritis.

Acid-sensing ion channel 1a (ASIC1a) is a member of the extracellular H+-activated cation channel family. Emerging evidence has suggested that ASIC1a plays a crucial role in the pathogenesis of rheumatoid arthritis (RA). Specifically, ASIC1a could promote inflammation, synovial hyperplasia, articular cartilage, and bone destruction; these lead to the progression of RA, a chronic autoimmune disease characterized by chronic synovial inflammation and extra-articular lesions. In this review, we provided a brief overview of the molecular properties of ASIC1a, including the basic biological characteristics, tissue and cell distribution, channel blocker, and factors influencing the expression and function, and focused on the potential therapeutic targets of ASIC1a in RA and possible mechanisms of blocking ASIC1a to improve RA symptoms, such as regulation of apoptosis, autophagy, pyroptosis, and necroptosis of articular cartilage, and synovial inflammation and invasion of fibroblast-like cells in synovial tissue.