{"gene":"ASIC3","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2001,"finding":"DRASIC (ASIC3) is localized in multiple specialized sensory nerve endings in skin, and its genetic disruption alters mechanoreceptor sensitivity bidirectionally: loss of DRASIC increases sensitivity of light-touch mechanoreceptors but reduces sensitivity of noxious-pinch mechanoreceptors and acid/noxious-heat nociceptors. The data indicate DRASIC participates in heteromultimeric channel complexes in sensory neurons.","method":"Gene knockout mouse (DRASIC-/−), immunolocalization in skin nerve endings, single-fiber electrophysiology","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular phenotype, direct localization, replicated across multiple sensory fiber types in one rigorous study","pmids":["11754838"],"is_preprint":false},{"year":2000,"finding":"ASIC2a and ASIC3 subunits co-assemble into heteromeric proton-gated cation channels: co-expression in Xenopus oocytes produces currents up to 20-fold larger than homomers, with a reversal potential reflecting Na+-selective current, and co-purification from HEK293 cells confirms biochemical interaction. Heteromeric ASIC2a/3 channels show increased sensitivity to Gd3+ (IC50 ~40 µM) compared to ASIC2a homomers (IC50 ≥1 mM).","method":"Xenopus oocyte co-expression electrophysiology, co-purification/co-immunoprecipitation from HEK293 cells, in situ hybridization for co-localization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reconstitution in oocytes plus biochemical co-purification, multiple orthogonal methods","pmids":["10842183"],"is_preprint":false},{"year":2002,"finding":"DRASIC (ASIC3) contributes to the composition and properties of H+-gated currents in large-diameter DRG neurons: genetic disruption of DRASIC slows desensitization kinetics, decreases pH sensitivity, increases amiloride sensitivity, and alters FMRF-related peptide potentiation, indicating DRASIC forms heteromultimeric acid-activated channels with other DEG/ENaC subunits in these neurons.","method":"Whole-cell patch clamp on large DRG neurons from DRASIC-/− mice vs. wild-type","journal":"Journal of neurophysiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined electrophysiological phenotype, multiple current properties measured","pmids":["12037186"],"is_preprint":false},{"year":2004,"finding":"APETx2, a 42-amino-acid peptide from sea anemone Anthopleura elegantissima, acts at the extracellular face of ASIC3 to reversibly inhibit rat ASIC3 homomeric channels (IC50 = 63 nM) and ASIC3-containing heteromeric channels, without affecting ASIC1a, ASIC1b, or ASIC2a. It does not change unitary conductance. It also inhibits the native ASIC3-like current in rat DRG neurons (IC50 = 216 nM).","method":"Electrophysiology in heterologous expression systems (Xenopus oocytes, HEK cells) and primary DRG neuron patch clamp; pharmacological characterization with outside-out patches","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct pharmacological characterization with multiple expression systems and native neurons, rigorous controls","pmids":["15044953"],"is_preprint":false},{"year":2004,"finding":"ASIC3 is regulated by protein kinase C (PKC) through its interaction with the silent ASIC2b subunit and the PDZ scaffold protein PICK-1. PKC stimulation (via phorbol ester PDBu or serotonin) increases native ASIC3-like currents in DRG neurons and shifts pH dependence toward more physiological values only in heteromeric ASIC3/ASIC2b channels (not ASIC3 homomers), requiring PICK-1 which binds the ASIC2b C-terminus.","method":"Whole-cell patch clamp of rat DRG neurons and heterologous expression, pharmacological PKC activation, PICK-1 interaction identified by PDZ domain analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — patch clamp in native neurons and heterologous system, multiple orthogonal approaches in one study, clear molecular dissection","pmids":["14976185"],"is_preprint":false},{"year":2004,"finding":"ASIC2 and ASIC3 null mutations do not alter mechanically activated currents (amplitude or kinetics) in isolated DRG neuron cell bodies, indicating that ASIC2 and ASIC3 are not required for mechanotransduction at the cell body level.","method":"Whole-cell patch clamp of cultured DRG neurons from ASIC2-/−, ASIC3-/−, and double-KO mice with mechanical stimulation","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO electrophysiology, explicit negative result replicated across multiple genotypes","pmids":["14990679"],"is_preprint":false},{"year":2006,"finding":"ASIC3 produces a sustained inward current within the pH range (7.3–6.7) that occurs during cardiac/skeletal muscle ischemia, because activation and inactivation curves overlap in this range. This sustained mode does not occur with ASIC1a homomers or ASIC1a/3 heteromers; ASIC2a/3 heteromers produce larger sustained currents than ASIC3 homomers. Lactate shifts activation to more basic pH; amiloride paradoxically increases ASIC3 current at pH 7.0. Cardiac sensory neurons exhibit a small perfectly sustained current at pH 7.0–7.4 that is potentiated by Zn2+ and amiloride.","method":"Patch clamp on transfected cell lines and fluorescently tagged cardiac sensory neurons; pH dose-response curves; pharmacological modulators","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstitution with pharmacological validation and native neuron recordings, multiple orthogonal approaches","pmids":["16873722"],"is_preprint":false},{"year":2006,"finding":"ASIC3 in primary afferent fibers innervating muscle (not skin) is required for development of cutaneous mechanical hyperalgesia after carrageenan-induced muscle inflammation. Rescue of the phenotype by herpes virus-mediated ASIC3 expression specifically in muscle (not skin) of ASIC3-/− mice restores mechanical hyperalgesia, establishing peripheral muscle ASIC3 as the critical locus.","method":"ASIC3-/− mice, behavioral pain testing (mechanical and heat), herpes virus vector-mediated tissue-specific ASIC3 re-expression, DRG mRNA/protein confirmation","journal":"Pain","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO plus tissue-specific genetic rescue experiment, multiple behavioral modalities","pmids":["17134831"],"is_preprint":false},{"year":2008,"finding":"PSD-95 interacts with ASIC3 via its PDZ domain and reduces ASIC3 cell surface expression and H+-gated current. ASIC3 and PSD-95 co-immunoprecipitate within lipid raft (detergent-resistant membrane) fractions; disruption of lipid rafts with methyl-β-cyclodextrin abolishes PSD-95 inhibition of ASIC3. Mutation of palmitoylation sites (Cys residues) in PSD-95 prevents its targeting to lipid rafts and its inhibition of ASIC3. Cell surface ASIC3 is enriched in lipid raft fractions.","method":"Co-immunoprecipitation, detergent-resistant membrane fractionation, methyl-β-cyclodextrin cholesterol depletion, site-directed mutagenesis of PSD-95 palmitoylation sites, whole-cell patch clamp","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (Co-IP, fractionation, mutagenesis, electrophysiology) in one study","pmids":["18579798"],"is_preprint":false},{"year":2008,"finding":"SMAD3 acts as a transcriptional repressor of the ASIC3 gene in nucleus pulposus cells. TGF-β treatment decreases ASIC3 mRNA/protein; constitutively active ALK5 or SMAD3 suppresses ASIC3 promoter activity; dominant-negative SMAD3 or SMAD7 restores it. SMAD3 directly binds two CAGA box motifs in the rat ASIC3 promoter as shown by gel-shift, supershift, and chromatin immunoprecipitation assays. Suppression requires histone deacetylase recruitment.","method":"Luciferase reporter assays, dominant-negative/constitutively active constructs, EMSA/supershift, ChIP, smad3-null cell rescue","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (reporter assay, EMSA, ChIP, null cell rescue) in one rigorous study","pmids":["18466073"],"is_preprint":false},{"year":2007,"finding":"p75NTR and ERK signaling maintain basal ASIC3 expression in nucleus pulposus cells: blocking p75NTR suppresses basal ASIC3 promoter activity; dominant-negative MEK suppresses, while constitutively active MEK1 increases, ASIC3 promoter activity. ASIC3 promotes disc cell survival under acidic and hyperosmotic conditions by lowering caspase-3 activity.","method":"Luciferase reporter assays, dominant-negative/constitutively active MEK, p75NTR blocking antibody/dominant-negative construct, MTT and caspase-3 activity assays","journal":"Journal of bone and mineral research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple reporter and pharmacological approaches in single lab study","pmids":["17696763"],"is_preprint":false},{"year":2009,"finding":"ASIC2a and ASIC3 are the major ASIC subunits forming heteromers in cardiac dorsal root ganglia neurons. Patch-clamp studies in cardiac afferents from ASIC3-/− mice show currents matching ASIC2a homomers; ASIC2-/− cardiac afferents show currents matching ASIC3 channels. Current properties of wild-type cardiac DRG neurons most closely match ASIC2a/3 heteromeric channels.","method":"Retrograde labeling + patch clamp in cardiac afferents from ASIC-null mice; pharmacological and kinetic characterization","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic ablation in native neurons with multiple ASIC-null genotypes, functional characterization","pmids":["19590043"],"is_preprint":false},{"year":2012,"finding":"ASIC1a, ASIC2a, and ASIC3 form heteromeric channels as the principal ASICs in skeletal muscle afferents. ASIC1a-/− currents show reduced pH sensitivity and faster recovery; ASIC2-/− currents show diminished Zn2+ potentiation; ASIC3-/− currents show slower desensitization. ASIC-like currents are absent in triple-null (ASIC1a/2a/3) mice.","method":"Patch clamp of isolated labeled mouse muscle afferents from specific ASIC-/− mice; pharmacological modulation","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic genetic dissection with multiple single and triple KO mice, patch clamp in native neurons","pmids":["23109675"],"is_preprint":false},{"year":2012,"finding":"Simultaneous knockout of ASIC1a, ASIC2, and ASIC3 (triple-KO) increases cutaneous mechanosensitivity: triple-KO mice show increased paw withdrawal frequency to von Frey filaments and enhanced single-fiber A-mechanonociceptor responses compared to wild-type. Other fiber types are unaffected. This indicates ASIC subunits influence mechanosensitivity but likely do not directly transduce mechanical stimuli.","method":"Triple-KO behavioral testing (von Frey), single-fiber cutaneous nerve recordings","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean genetic ablation with behavioral and electrophysiological phenotyping in single study","pmids":["22506072"],"is_preprint":false},{"year":2016,"finding":"ASIC3 is expressed in parvalbumin-positive (Pv+) proprioceptor axons innervating muscle spindles. Conditional knockout of ASIC3 in Pv+ neurons disrupts spindle afferent sensitivity to dynamic stimuli and impairs mechanotransduction in Pv+ DRG neurons in response to substrate deformation-induced neurite stretching, but not direct neurite indentation. Global and Pv-Cre::Asic3f/f mice show similar deficits in grid and balance beam walking tasks.","method":"Asic3-KO/eGFPf-knockin mice, Cre-lox conditional KO, electrophysiology of muscle spindle afferents, localized elastic matrix mechanostimulation, behavioral tasks","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO, spindle afferent electrophysiology, cell-specific mechanostimulation, behavioral validation","pmids":["27161260"],"is_preprint":false},{"year":2016,"finding":"ASIC3 in cerebrospinal fluid-contacting neurons of lamprey spinal cord mediates both mechanosensory and chemosensory (pH) responses. APETx2 (selective ASIC3 antagonist) blocks both mechanical stimulation-evoked and low-pH-evoked responses in these neurons. Lowering pH or applying somatostatin reduces locomotor burst rate; somatostatin receptor antagonist counteracts both effects.","method":"Whole-cell patch clamp of identified CSF-contacting neurons, APETx2 pharmacological blockade, imposed lateral bending, pH manipulation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct pharmacological blockade with APETx2 in native neurons with both mechanical and chemical stimuli","pmids":["26743691"],"is_preprint":false},{"year":2013,"finding":"Sea anemone peptide Ugr 9-1 (π-AnmTX Ugr 9a-1) reversibly inhibits human ASIC3 expressed in Xenopus oocytes: it completely blocks the transient current component (IC50 10 µM) and partially inhibits the sustained component (IC50 1.44 µM). NMR spectroscopy revealed a novel 'boundless β-hairpin' structure stabilized by two disulfide bonds.","method":"Xenopus oocyte electrophysiology, NMR structure determination, in vivo pain assays in mice","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro electrophysiology plus NMR structural characterization in one study","pmids":["23801332"],"is_preprint":false},{"year":2017,"finding":"ASIC3 and P2X3 receptors physically associate to form a multiprotein complex in sensory neurons. ASIC3 stimulation strongly inhibits P2X3R current partly through a Ca2+-dependent mechanism. The proton-binding site of ASIC3 is critical for this inhibitory effect. Co-immunoprecipitation and BN-PAGE/SDS-PAGE analysis are consistent with a heteromeric multiprotein structure (though not a single heteromeric channel). The two receptors switch their ionic permeabilities during activation.","method":"Patch clamp current measurements, co-immunoprecipitation, BN-PAGE, SDS-PAGE, Ca2+ chelation experiments, in vivo pain summation in rats","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, BN-PAGE, and electrophysiology as multiple orthogonal methods","pmids":["29636447"],"is_preprint":false},{"year":2017,"finding":"RPRFamide (a 4-amino acid cono-RFamide from Conus textile venom) strongly potentiates ASIC3 currents and increases DRG neuron excitability. Injection into mouse gastrocnemius muscle enhances acid-induced muscle pain, and this enhancement is abolished by genetic inactivation of ASIC3.","method":"In vitro venom screen electrophysiology, patch clamp of isolated DRG neurons, ASIC3-/− mouse in vivo pain assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — electrophysiology in native neurons plus genetic KO validation","pmids":["28396446"],"is_preprint":false},{"year":2017,"finding":"ASIC1 and ASIC3 mediate acidity-induced epithelial-mesenchymal transition (EMT) in pancreatic cancer cells through a Ca2+/RhoA pathway. Acid-induced inward current via ASIC1/ASIC3 elevates intracellular Ca2+, which activates RhoA downstream; siRNA knockdown or pharmacological inhibition of ASIC1/ASIC3 decreases [Ca2+]i and RhoA, suppressing EMT. ASIC1/ASIC3 knockdown suppresses liver and lung metastasis in xenograft models.","method":"siRNA knockdown, pharmacological inhibition, Ca2+ imaging, RhoA assay, xenograft metastasis model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional knockdown with multiple downstream pathway readouts and in vivo validation, single lab","pmids":["28518134"],"is_preprint":false},{"year":2015,"finding":"ASIC3 mediates itch sensation via coincident detection of acidosis and nonproton ligands (SL-NH2). Co-administration of acid with SL-NH2 increases scratching in wild-type but not ASIC3-null mice. Mechanistically, SL-NH2 slows desensitization of proton-evoked currents by targeting the nonproton ligand-sensing domain in the extracellular region of ASIC3. ASIC3 gene ablation also reduces dry-skin-induced scratching.","method":"ASIC3-/− behavioral assay, patch clamp on primary sensory neurons, mutagenesis of nonproton ligand-sensing domain","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO behavioral phenotype plus electrophysiology with domain-level mechanistic dissection","pmids":["26440887"],"is_preprint":false},{"year":2017,"finding":"PAR2 signaling sensitizes ASIC3 via an intracellular cascade involving G protein, PLC, PKC, and PKA. PAR2-activating peptide concentration-dependently increases ASIC3 currents in CHO cells expressing both ASIC3 and PAR2, increasing maximal response by ~59% without changing pH50. PAR2 activation also increases proton-evoked currents and spikes in rat DRG neurons. Inhibition of each signaling step (G protein, PLC, PKC, or PKA) abolishes PAR2-induced potentiation of ASIC3.","method":"Whole-cell patch clamp in CHO cells and DRG neurons, pharmacological inhibition of G protein/PLC/PKC/PKA","journal":"Journal of neuroinflammation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — systematic pharmacological dissection of signaling cascade in both heterologous and native cells","pmids":["28754162"],"is_preprint":false},{"year":2016,"finding":"ASIC2a co-expression increases ASIC3 surface expression via heteromeric assembly, markedly enhancing the sustained component of proton-evoked currents. ASIC3 alone is largely retained in the ER; co-expression with ASIC2a drives plasma membrane targeting. Heteromeric association confirmed by BiFC assay.","method":"Surface biotinylation, bimolecular fluorescence complementation (BiFC), whole-cell patch clamp in heterologous cells","journal":"BMB reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — BiFC plus electrophysiology in single lab, heterologous expression system","pmids":["27241858"],"is_preprint":false},{"year":2012,"finding":"CAR (Coxsackievirus and adenovirus receptor) interacts with ASIC3 only when PSD-95 is co-expressed, and CAR recruits both PSD-95 and ASIC3 to cell-cell junctions. Furthermore, CAR rescues PSD-95-mediated inhibition of ASIC3 currents, indicating CAR can modulate ASIC3 trafficking through a PDZ-based scaffolding complex.","method":"Co-immunoprecipitation, immunofluorescence localization, whole-cell patch clamp in heterologous cells","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, localization, and electrophysiology in heterologous cells, single lab","pmids":["22809504"],"is_preprint":false},{"year":2021,"finding":"Amiloride exerts paradoxical potentiation of ASIC3 sustained currents at neutral pH while inhibiting currents at acidic pH. Mechanistically, amiloride causes alkaline shift of pH-dependent activation, inhibits steady-state desensitization (SSD), and requires extracellular Ca2+. Site-directed mutagenesis identifies E79 and E423 in the nonproton ligand-sensing domain as critical for amiloride-induced inhibition of SSD; disruption of the pore amiloride binding site (G445C) blunts both inhibition and potentiation.","method":"Whole-cell patch clamp, site-directed mutagenesis of ASIC3 expressed in heterologous cells","journal":"Frontiers in physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution with systematic mutagenesis of multiple residues plus rigorous electrophysiological characterization","pmids":["34721074"],"is_preprint":false},{"year":2023,"finding":"Multiscale MD simulations predict arachidonic acid (AA) binds the outer leaflet transmembrane region of ASIC3, with salt bridge interactions at R65 and R68 and aromatic interactions at Y58 in hASIC3. Subtle differences exist between ASIC1a and ASIC3 AA interaction patterns reversible by mutating three key residues at the outer TM1 leaflet. Longer, more unsaturated fatty acid tails show increased occupancy at this region.","method":"Multiscale molecular dynamics simulations, mutagenesis analysis in silico","journal":"The Journal of general physiology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational prediction only, no experimental functional validation reported in this paper","pmids":["36625864"],"is_preprint":false},{"year":2016,"finding":"IL-1β from ischemic muscle upregulates ASIC3 in single muscle afferent neurons (DRG), and nerve-specific knockdown of ASIC3 recapitulates the effects of inhibiting IL1β/IL1R signaling, reversing sensitization of group III/IV afferents and pain behaviors after ischemia-reperfusion injury. This establishes an IL1β → IL1R → ASIC3 signaling axis in muscle afferents mediating ischemic myalgia.","method":"In vitro IL-1β treatment of single DRG neurons, siRNA nerve-specific knockdown in vivo, afferent single-unit recordings, behavioral pain assays","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — single-cell in vitro mechanism combined with nerve-specific KD and in vivo functional readouts","pmids":["27358445"],"is_preprint":false},{"year":2019,"finding":"ASIC3 interacts with HIF-1α and ERK1/2 as shown by co-immunoprecipitation in nucleus pulposus cells. Hypoxia-induced ASIC3 upregulation is reduced by HIF-1α silencing, indicating mutual regulation. ASIC3 overexpression under hypoxia activates MAPK/ERK pathway, inhibits proliferation, arrests cell cycle in G1, and promotes apoptosis and autophagy; ASIC3 silencing reverses these effects.","method":"Co-immunoprecipitation, shRNA knockdown, ASIC3 overexpression, flow cytometry, western blot, CCK-8, transmission EM","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP for interaction, functional knockdown/OE with multiple cellular readouts, single lab","pmids":["31202172"],"is_preprint":false},{"year":2024,"finding":"ASIC3 activation in nociceptors exacerbates psoriatic inflammation through a neurogenic pathway. Global or nociceptor-specific Asic3 KO in female mice alleviates imiquimod-induced psoriatic acanthosis and type 17 inflammation similarly to nociceptor ablation. Mechanistically, ASIC3 activation induces activity-dependent release of CGRP from sensory neurons to promote neurogenic inflammation; CGRP replenishment in skin of Asic3-KO mice restores the inflammatory response. Botulinum neurotoxin A and CGRP antagonists phenocopy Asic3 KO.","method":"Global and nociceptor-specific conditional KO, imiquimod-induced psoriasis model, CGRP rescue experiment, botulinum toxin, CGRP antagonists, histology","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO, mechanistic rescue with CGRP, pharmacological validation with multiple agents in one study","pmids":["38902277"],"is_preprint":false},{"year":2022,"finding":"ASIC3 activation promotes M-CSF transcriptional regulation in macrophages, driving M2 polarization. M2 macrophages transduced by the ASIC3-M-CSF signal promote fibroblast-to-myofibroblast differentiation through TGF-β1, forming an ASIC3-M-CSF-TGF-β1 positive feedback loop in skin fibrosis.","method":"ASIC3 activation/inhibition in cultured cells, western blot, cytokine/macrophage polarization assays, fibroblast differentiation assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional cell biology with pathway dissection, single lab, primarily in vitro","pmids":["35661105"],"is_preprint":false},{"year":2008,"finding":"17β-estradiol (E2) upregulates ASIC3 protein expression in a dose- and time-dependent manner via estrogen receptor α (ERα); the ERα-specific antagonist MPP blocks this effect. Female rats have higher ASIC3 expression in DRG than males; ovariectomy decreases DRG ASIC3 expression; orchiectomy does not affect it.","method":"Co-transfection of ASIC3 and ERα in 293T cells with western blot, ERα antagonist MPP, in vivo ovariectomy/orchiectomy with DRG western blot","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — heterologous system with pharmacological blockade plus in vivo hormonal manipulation, single lab","pmids":["30114476"],"is_preprint":false},{"year":2012,"finding":"ASIC3 expression is increased ~2-fold in knee joint afferents in rats with monoiodoacetate-induced osteoarthritis. Continuous intra-articular injection of APETx2 (ASIC3 blocker) inhibits weight-bearing pain, secondary hyperalgesia, and attenuates ASIC3 upregulation in joint afferents. Early APETx2 administration has chondroprotective effects.","method":"Immunohistochemistry, behavioral pain testing, intra-articular APETx2 injection, histology","journal":"Journal of biomedical science","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological block in vivo with behavioral and immunohistochemical readouts, single lab","pmids":["22909215"],"is_preprint":false},{"year":2010,"finding":"ASIC3-like current in carotid body glomus cells mediates acidosis chemosensitivity. Increased ASIC3 expression in transgenic mice increases pH sensitivity while reducing cyanide/hypoxia sensitivity; ASIC3 deletion reduces pH sensitivity while increasing relative sensitivity to hypoxia. This reciprocal relationship demonstrates ASIC3 is a specific molecular determinant of acidosis chemotransduction in glomus cells.","method":"Ca2+ imaging in isolated glomus cells, ASIC3 transgenic and KO mice, pharmacological and hypoxia stimulation","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — transgenic gain and loss of function with functional Ca2+ measurements in native cells","pmids":["23165770"],"is_preprint":false},{"year":2023,"finding":"ASIC3 is required for immediate exercise-induced pain (IEIP) but plays a protective role against muscle injury during strenuous exercise. ASIC3-/− mice do not develop reduced muscle withdrawal threshold immediately after exhaustive exercise (no IEIP). At 24 h, ASIC3-/− mice show lower locomotor activity, lower repeat exercise performance, and higher serum markers of muscle injury (LDH, CK) than wild-type mice.","method":"ASIC3-/− mice, treadmill exercise, muscle withdrawal threshold, locomotor testing, grip strength, serum enzyme assays","journal":"Frontiers in pain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with multiple functional outcome measures, single lab","pmids":["37795390"],"is_preprint":false}],"current_model":"ASIC3 (also known as DRASIC, TNaC1, ACCN3) is a proton-gated, Na+-selective cation channel of the DEG/ENaC superfamily expressed predominantly in peripheral sensory neurons, where it functions as a sensitive detector of extracellular acidosis—including the mild, sustained pH drops (7.3–6.7) occurring during ischemia—by producing both transient and sustained inward currents; it forms heteromeric channels with ASIC2a and ASIC2b subunits (the latter requiring PICK-1 scaffold for PKC-dependent upregulation), is regulated at the plasma membrane by PSD-95 within lipid rafts, by CAR-mediated trafficking, and by estrogen receptor α-mediated transcriptional control; it acts via a Ca2+/RhoA pathway in non-neuronal cells and via CGRP release from nociceptors in neurogenic inflammation; it contributes to mechanosensory transduction in proprioceptors (muscle spindle dynamic sensitivity) and coincident detection of acid plus nonproton ligands to mediate itch; and its activity can be selectively blocked by APETx2 or potentiated by RPRFamide, cono-RFamides, and amiloride (paradoxically at neutral pH via the nonproton ligand-sensing domain)."},"narrative":{"mechanistic_narrative":"ASIC3 is a proton-gated, Na+-selective cation channel of the DEG/ENaC superfamily that functions in peripheral sensory neurons as a detector of extracellular acidosis and contributes to nociception, mechanosensation, and chemosensation [PMID:11754838, PMID:12037186]. It distinctively produces a sustained inward current within the mild pH range (7.3–6.7) characteristic of cardiac and skeletal muscle ischemia, because its activation and inactivation curves overlap in this window; lactate, Zn2+, and amiloride further modulate this sustained mode [PMID:16873722]. ASIC3 rarely acts as a homomer in vivo: it co-assembles into heteromeric channels with ASIC2a and ASIC2b that determine current amplitude, kinetics, pH sensitivity, and surface expression [PMID:10842183, PMID:19590043, PMID:23109675, PMID:27241858], and genetic dissection in cardiac and skeletal muscle afferents confirms ASIC2a/3 (and ASIC1a/2a/3) heteromers as the principal native channels [PMID:19590043, PMID:23109675]. Channel activity is tuned by intracellular scaffolds and kinases—PICK-1 enables PKC-dependent potentiation of ASIC3/ASIC2b channels, PSD-95 within lipid rafts reduces surface expression and current, and CAR modulates trafficking through this PDZ-based complex [PMID:14976185, PMID:18579798, PMID:22809504]—and is further sensitized by PAR2 signaling through a G protein/PLC/PKC/PKA cascade [PMID:28754162]. In sensory physiology, muscle ASIC3 drives inflammatory mechanical hyperalgesia and ischemic myalgia via an IL-1β→IL-1R axis [PMID:17134831, PMID:27358445], contributes to proprioceptor and muscle-spindle dynamic sensitivity [PMID:27161260], mediates immediate exercise-induced pain while protecting against muscle injury [PMID:37795390], and mediates acid-plus-nonproton-ligand coincident detection underlying itch [PMID:26440887]. Beyond neurons, ASIC3 acts via Ca2+/RhoA signaling in pancreatic cancer EMT and metastasis [PMID:28518134] and drives CGRP-dependent neurogenic inflammation in psoriasis [PMID:38902277]. ASIC3 expression is transcriptionally controlled by SMAD3 repression, p75NTR/ERK maintenance, and estrogen-receptor-α induction [PMID:18466073, PMID:17696763, PMID:30114476]. Pharmacologically, the sea anemone peptide APETx2 selectively inhibits ASIC3, RFamide peptides potentiate it, and amiloride paradoxically potentiates the sustained current at neutral pH through the nonproton ligand-sensing domain [PMID:15044953, PMID:28396446, PMID:34721074].","teleology":[{"year":2000,"claim":"Established that ASIC3 is not an obligate homomer but co-assembles with ASIC2a into proton-gated heteromers, answering how subunit composition sets channel properties.","evidence":"Xenopus oocyte co-expression electrophysiology plus co-purification from HEK293 cells","pmids":["10842183"],"confidence":"High","gaps":["Stoichiometry of the heteromer not resolved","Did not establish native composition in sensory neurons"]},{"year":2001,"claim":"Defined ASIC3's in vivo sensory role by showing its loss bidirectionally alters mechanoreceptor and acid/heat nociceptor sensitivity, implicating it in heteromeric channels in sensory endings.","evidence":"DRASIC-/- knockout mouse with skin immunolocalization and single-fiber recordings","pmids":["11754838"],"confidence":"High","gaps":["Did not identify the specific heteromeric partners in each fiber type","Mechanism of mechanoreceptor modulation unresolved"]},{"year":2002,"claim":"Showed ASIC3 shapes the kinetics, pH sensitivity, and pharmacology of native DRG H+-gated currents, confirming it forms heteromultimeric acid-sensors in sensory neurons.","evidence":"Whole-cell patch clamp of large DRG neurons from DRASIC-/- vs wild-type mice","pmids":["12037186"],"confidence":"High","gaps":["Partner subunits in large DRG neurons not biochemically defined"]},{"year":2004,"claim":"Identified APETx2 as a selective ASIC3 antagonist, providing the key pharmacological tool to probe native ASIC3 currents.","evidence":"Electrophysiology in oocytes, HEK cells, and rat DRG neurons with outside-out patches","pmids":["15044953"],"confidence":"High","gaps":["Binding site on ASIC3 not mapped","Cross-reactivity in mixed heteromers incompletely characterized"]},{"year":2004,"claim":"Resolved how kinase signaling tunes ASIC3 by showing PKC potentiates ASIC3/ASIC2b channels via the PICK-1 scaffold binding the ASIC2b C-terminus.","evidence":"Patch clamp of DRG and heterologous cells with PKC activation and PDZ-domain interaction analysis","pmids":["14976185"],"confidence":"High","gaps":["Phosphorylation site on the channel not identified","Whether PKC acts directly on ASIC3 or via PICK-1 unresolved"]},{"year":2004,"claim":"Distinguished cell-body mechanotransduction from sensory-ending function by showing ASIC2/ASIC3 are dispensable for mechanically activated currents in DRG somata.","evidence":"Patch clamp of cultured DRG neurons from single and double KO mice with mechanical stimulation","pmids":["14990679"],"confidence":"High","gaps":["Negative result does not exclude a role at peripheral endings","Possible compensation by other channels not addressed"]},{"year":2006,"claim":"Explained ASIC3's ischemia-sensing capacity by demonstrating a sustained current in the mild pH range where activation and inactivation overlap, enhanced in ASIC2a/3 heteromers.","evidence":"Patch clamp of transfected lines and cardiac sensory neurons with pH dose-response and pharmacology","pmids":["16873722"],"confidence":"High","gaps":["Molecular basis of overlapping activation/inactivation curves not structurally defined","Contribution of endogenous lactate in vivo not quantified"]},{"year":2006,"claim":"Localized the critical site of inflammatory mechanical hyperalgesia to muscle ASIC3 using tissue-specific genetic rescue.","evidence":"ASIC3-/- mice with herpesvirus-mediated muscle-specific re-expression and behavioral testing","pmids":["17134831"],"confidence":"High","gaps":["Downstream central sensitization mechanism not defined","Did not identify the proton/inflammatory trigger in muscle"]},{"year":2007,"claim":"Linked ASIC3 expression and cell survival in nucleus pulposus to p75NTR/ERK signaling, extending ASIC3 function beyond neurons.","evidence":"Luciferase reporters, dominant-negative/constitutively active MEK, p75NTR blockade, caspase-3 assays","pmids":["17696763"],"confidence":"Medium","gaps":["Single-lab reporter-based study","Direct transcription factor binding not shown"]},{"year":2008,"claim":"Established transcriptional repression of ASIC3 by SMAD3 downstream of TGF-β, defining a direct promoter-level control mechanism.","evidence":"Reporter assays, EMSA/supershift, ChIP, and smad3-null cell rescue in nucleus pulposus cells","pmids":["18466073"],"confidence":"High","gaps":["Relevance to neuronal ASIC3 regulation not tested","HDAC partner identity not specified"]},{"year":2008,"claim":"Showed PSD-95 within lipid rafts is a negative regulator of ASIC3 surface expression and current, revealing membrane-microdomain control.","evidence":"Co-IP, detergent-resistant membrane fractionation, cholesterol depletion, PSD-95 palmitoylation mutagenesis, patch clamp","pmids":["18579798"],"confidence":"High","gaps":["In vivo relevance in sensory neurons not established","Mechanism by which raft localization reduces current unclear"]},{"year":2009,"claim":"Defined the major native cardiac afferent ASIC as the ASIC2a/3 heteromer using complementary genetic ablations.","evidence":"Retrograde labeling and patch clamp in cardiac afferents from ASIC2-/- and ASIC3-/- mice","pmids":["19590043"],"confidence":"High","gaps":["Heteromer stoichiometry not determined","Contribution to cardiac pain perception in vivo not directly measured here"]},{"year":2010,"claim":"Identified ASIC3 as a specific molecular determinant of acidosis chemotransduction in carotid body glomus cells via reciprocal gain/loss of function.","evidence":"Ca2+ imaging in glomus cells from ASIC3 transgenic and KO mice with pH and hypoxia stimulation","pmids":["23165770"],"confidence":"High","gaps":["Heteromeric partners in glomus cells not defined","Link to ventilatory output not directly tested"]},{"year":2012,"claim":"Demonstrated ASIC1a/2a/3 heteromers are the principal acid sensors of skeletal muscle afferents through systematic single and triple knockouts.","evidence":"Patch clamp of labeled muscle afferents from multiple ASIC-null genotypes","pmids":["23109675"],"confidence":"High","gaps":["Subunit ratio within native heteromers unknown"]},{"year":2012,"claim":"Clarified that ASIC subunits influence but do not directly transduce cutaneous mechanical stimuli, since triple-KO increases mechanosensitivity.","evidence":"Triple-KO von Frey behavior and single-fiber cutaneous recordings","pmids":["22506072"],"confidence":"High","gaps":["Identity of the actual mechanotransducer remains open","Mechanism of the modulatory effect unresolved"]},{"year":2012,"claim":"Showed CAR recruits ASIC3 and PSD-95 to cell-cell junctions and can rescue PSD-95-mediated inhibition, adding a trafficking layer to the PDZ scaffold network.","evidence":"Co-IP, immunofluorescence, and patch clamp in heterologous cells","pmids":["22809504"],"confidence":"Medium","gaps":["Heterologous system only","Physiological context in sensory neurons untested"]},{"year":2012,"claim":"Provided in vivo evidence for ASIC3 in osteoarthritic joint pain and a candidate chondroprotective role using APETx2 blockade.","evidence":"Immunohistochemistry, behavioral pain testing, and intra-articular APETx2 in a monoiodoacetate OA model","pmids":["22909215"],"confidence":"Medium","gaps":["Single-lab pharmacology","Cellular mechanism of chondroprotection unclear"]},{"year":2013,"claim":"Characterized Ugr 9-1 as a structurally novel ASIC3 inhibitor that differentially blocks transient versus sustained current components.","evidence":"Xenopus oocyte electrophysiology, NMR structure, and mouse pain assays","pmids":["23801332"],"confidence":"High","gaps":["Binding site on ASIC3 not mapped","Selectivity across heteromers not fully tested"]},{"year":2015,"claim":"Revealed ASIC3 mediates itch via coincident detection of acid and the nonproton ligand SL-NH2 acting on an extracellular ligand-sensing domain.","evidence":"ASIC3-/- scratching behavior, patch clamp, and nonproton ligand-sensing domain mutagenesis","pmids":["26440887"],"confidence":"High","gaps":["Endogenous nonproton ligand in itch not identified","Downstream itch circuitry not defined"]},{"year":2016,"claim":"Established muscle ASIC3 as a node in an IL-1β→IL-1R axis driving ischemic myalgia through afferent sensitization.","evidence":"IL-1β treatment of single DRG neurons, nerve-specific siRNA knockdown, single-unit recordings, behavior","pmids":["27358445"],"confidence":"High","gaps":["Transcriptional mechanism of IL-1β-induced ASIC3 upregulation not defined"]},{"year":2016,"claim":"Defined ASIC3 in proprioceptor axons as a contributor to muscle-spindle dynamic sensitivity and stretch-dependent mechanotransduction.","evidence":"Asic3 conditional KO in Pv+ neurons, spindle afferent electrophysiology, elastic-matrix stimulation, behavior","pmids":["27161260"],"confidence":"High","gaps":["Whether ASIC3 directly transduces stretch or modulates a transducer unresolved"]},{"year":2016,"claim":"Demonstrated dual mechano- and chemosensory ASIC3 function in lamprey CSF-contacting neurons using APETx2 blockade.","evidence":"Patch clamp of identified CSF-contacting neurons with APETx2, mechanical bending, and pH manipulation","pmids":["26743691"],"confidence":"High","gaps":["Mechanism of mechanical gating in these neurons not defined","Conservation to mammalian CSF-contacting neurons not shown"]},{"year":2016,"claim":"Showed ASIC2a co-expression rescues ASIC3 from ER retention, driving surface targeting and enhancing the sustained current.","evidence":"Surface biotinylation, BiFC, and patch clamp in heterologous cells","pmids":["27241858"],"confidence":"Medium","gaps":["Heterologous system only","ER retention signal on ASIC3 not mapped"]},{"year":2017,"claim":"Identified a physical and functional ASIC3–P2X3 complex in which ASIC3 activation inhibits P2X3 current via a Ca2+-dependent mechanism.","evidence":"Patch clamp, reciprocal Co-IP, BN-PAGE/SDS-PAGE, Ca2+ chelation, in vivo pain summation","pmids":["29636447"],"confidence":"High","gaps":["Structural basis of the complex unresolved","Not a single heteromeric channel; interface undefined"]},{"year":2017,"claim":"Characterized the cono-RFamide RPRFamide as a potentiator of ASIC3 that enhances acid-induced muscle pain in an ASIC3-dependent manner.","evidence":"Venom electrophysiology, DRG patch clamp, and ASIC3-/- in vivo pain assay","pmids":["28396446"],"confidence":"High","gaps":["Binding site for RFamide peptides not mapped","Endogenous mammalian RFamide relevance not addressed"]},{"year":2017,"claim":"Defined PAR2 as a sensitizer of ASIC3 acting through a G protein/PLC/PKC/PKA cascade in heterologous and native neurons.","evidence":"Patch clamp in CHO cells and DRG neurons with stepwise pharmacological inhibition","pmids":["28754162"],"confidence":"High","gaps":["Direct phosphorylation target on ASIC3 not identified"]},{"year":2017,"claim":"Extended ASIC3 function to cancer biology, showing ASIC1/ASIC3 mediate acidity-induced EMT and metastasis via a Ca2+/RhoA pathway.","evidence":"siRNA knockdown, pharmacological inhibition, Ca2+ imaging, RhoA assay, xenograft metastasis","pmids":["28518134"],"confidence":"Medium","gaps":["Single-lab study","Relative contribution of ASIC1 vs ASIC3 not dissected"]},{"year":2018,"claim":"Connected ASIC3 to sex-dependent expression by showing estrogen-receptor-α-mediated upregulation of ASIC3 protein.","evidence":"Co-transfection western blot with ERα antagonist and in vivo ovariectomy/orchiectomy","pmids":["30114476"],"confidence":"Medium","gaps":["Whether ERα acts at the ASIC3 promoter directly not shown","Functional consequence for pain not measured here"]},{"year":2019,"claim":"Implicated ASIC3 in hypoxic nucleus pulposus cell fate through interaction with HIF-1α and ERK1/2 and downstream MAPK/ERK-driven apoptosis and autophagy.","evidence":"Co-IP, shRNA knockdown, overexpression, flow cytometry, western blot, EM","pmids":["31202172"],"confidence":"Medium","gaps":["Single-lab correlative interaction data","Direct vs indirect HIF-1α interaction unclear"]},{"year":2021,"claim":"Mechanistically dissected amiloride's paradoxical potentiation of ASIC3 sustained current at neutral pH, mapping it to nonproton ligand-sensing residues E79/E423 and the pore site G445.","evidence":"Patch clamp with systematic site-directed mutagenesis in heterologous cells","pmids":["34721074"],"confidence":"High","gaps":["Structural model of dual amiloride action not resolved","Physiological relevance of neutral-pH potentiation untested"]},{"year":2022,"claim":"Implicated ASIC3 in skin fibrosis through an ASIC3–M-CSF–TGF-β1 positive feedback loop driving M2 macrophage polarization and myofibroblast differentiation.","evidence":"ASIC3 activation/inhibition in cultured cells, macrophage polarization and fibroblast differentiation assays","pmids":["35661105"],"confidence":"Medium","gaps":["Primarily in vitro","How acid activation occurs in fibrotic tissue not defined"]},{"year":2023,"claim":"Defined a dual role for ASIC3 in exercise: required for immediate exercise-induced pain but protective against strenuous-exercise muscle injury.","evidence":"ASIC3-/- mice with treadmill exercise, withdrawal threshold, locomotor and grip testing, serum injury markers","pmids":["37795390"],"confidence":"Medium","gaps":["Mechanism of protection against muscle injury not defined","Single-lab study"]},{"year":2023,"claim":"Predicted a transmembrane arachidonic-acid binding site on ASIC3 involving R65, R68, and Y58, proposing lipid modulation of the channel.","evidence":"Multiscale molecular dynamics simulations with in silico mutagenesis","pmids":["36625864"],"confidence":"Low","gaps":["Computational prediction without experimental functional validation","Functional effect of AA binding on ASIC3 not measured"]},{"year":2024,"claim":"Established ASIC3 as a driver of neurogenic psoriatic inflammation through activity-dependent CGRP release from nociceptors.","evidence":"Global and nociceptor-specific conditional KO, imiquimod psoriasis model, CGRP rescue, botulinum toxin, CGRP antagonists","pmids":["38902277"],"confidence":"High","gaps":["Endogenous acidic/ligand trigger in psoriatic skin not defined","Sex-specificity of the effect not fully explained"]},{"year":null,"claim":"A high-resolution structural basis for ASIC3's overlapping activation/inactivation, heteromer interfaces, and the nonproton ligand-sensing domain that integrates protons, RFamides, and amiloride remains undefined.","evidence":"No structural study in the timeline resolves the full-length channel or its modulator binding sites","pmids":[],"confidence":"Low","gaps":["No experimental structure of ASIC3 or its heteromers","Subunit stoichiometry of native heteromers unresolved","Direct phosphorylation sites mediating kinase potentiation unmapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[20,24,6]},{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[1,6,11]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[8,22,23]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[22]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,2,6]},{"term_id":"R-HSA-9709957","term_label":"Sensory Perception","supporting_discovery_ids":[20,32,14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,21,19]}],"complexes":["ASIC2a/ASIC3 heteromeric channel","ASIC1a/ASIC2a/ASIC3 heteromeric channel","ASIC3/ASIC2b/PICK-1 complex","ASIC3–P2X3 multiprotein complex"],"partners":["ASIC2A","ASIC2B","ASIC1A","PICK1","DLG4","CXADR","P2RX3","HIF1A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UHC3","full_name":"Acid-sensing ion channel 3","aliases":["Amiloride-sensitive cation channel 3","Neuronal amiloride-sensitive cation channel 3","Testis sodium channel 1","hTNaC1"],"length_aa":531,"mass_kda":58.9,"function":"Forms pH-gated heterotrimeric sodium channels that act as postsynaptic excitatory receptors in the nervous system (PubMed:10842183, PubMed:11587714, PubMed:9744806, PubMed:9886053). Upon extracellular acidification, these channels generate a biphasic current with a fast inactivating and a slow sustained phase (PubMed:10842183, PubMed:9744806, PubMed:9886053). ASIC3 is more sensitive to protons and gates between closed, open, and desensitized states faster than other ASICs (By similarity). Displays high selectivity for sodium ions but can also permit the permeation of other cations (PubMed:9744806, PubMed:9886053). As a neuronal acid sensor, probably contributes to mechanoreception, acid nociception, and heat nociception (By similarity). By forming heterotrimeric channels with ASIC2, generates a biphasic current with a fast inactivating and a slow sustained phase, which in sensory neurons is proposed to mediate the pain induced by acidosis that occurs in ischemic, damaged or inflamed tissues (By similarity)","subcellular_location":"Cell membrane; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9UHC3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ASIC3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ASIC3","total_profiled":1310},"omim":[{"mim_id":"611741","title":"ACID-SENSING ION CHANNEL, SUBUNIT 3; ASIC3","url":"https://www.omim.org/entry/611741"},{"mim_id":"611549","title":"SODIUM LEAK CHANNEL, NONSELECTIVE; NALCN","url":"https://www.omim.org/entry/611549"},{"mim_id":"604775","title":"TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL, SUBFAMILY A, MEMBER 1; TRPA1","url":"https://www.omim.org/entry/604775"},{"mim_id":"602866","title":"ACID-SENSING ION CHANNEL, SUBUNIT 1; ASIC1","url":"https://www.omim.org/entry/602866"},{"mim_id":"602836","title":"PURINERGIC RECEPTOR P2X, LIGAND-GATED ION CHANNEL, 5; P2RX5","url":"https://www.omim.org/entry/602836"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":45.0}],"url":"https://www.proteinatlas.org/search/ASIC3"},"hgnc":{"alias_symbol":["TNaC1","DRASIC"],"prev_symbol":["ACCN3"]},"alphafold":{"accession":"Q9UHC3","domains":[{"cath_id":"1.10.287.770","chopping":"16-69_430-471","consensus_level":"high","plddt":88.4921,"start":16,"end":471},{"cath_id":"2.60.470.10","chopping":"72-94_156-224_240-285_369-424","consensus_level":"medium","plddt":94.2667,"start":72,"end":424}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UHC3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UHC3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UHC3-F1-predicted_aligned_error_v6.png","plddt_mean":82.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ASIC3","jax_strain_url":"https://www.jax.org/strain/search?query=ASIC3"},"sequence":{"accession":"Q9UHC3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UHC3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UHC3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UHC3"}},"corpus_meta":[{"pmid":"11754838","id":"PMC_11754838","title":"The DRASIC cation channel contributes to the detection of cutaneous touch and acid stimuli in mice.","date":"2001","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/11754838","citation_count":480,"is_preprint":false},{"pmid":"15044953","id":"PMC_15044953","title":"A new sea anemone peptide, APETx2, inhibits ASIC3, a major acid-sensitive channel in sensory neurons.","date":"2004","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/15044953","citation_count":306,"is_preprint":false},{"pmid":"12060708","id":"PMC_12060708","title":"A role for ASIC3 in the modulation of high-intensity pain stimuli.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12060708","citation_count":259,"is_preprint":false},{"pmid":"16873722","id":"PMC_16873722","title":"Sustained currents through ASIC3 ion channels at the modest pH changes that occur during myocardial 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The data indicate DRASIC participates in heteromultimeric channel complexes in sensory neurons.\",\n      \"method\": \"Gene knockout mouse (DRASIC-/−), immunolocalization in skin nerve endings, single-fiber electrophysiology\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular phenotype, direct localization, replicated across multiple sensory fiber types in one rigorous study\",\n      \"pmids\": [\"11754838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"ASIC2a and ASIC3 subunits co-assemble into heteromeric proton-gated cation channels: co-expression in Xenopus oocytes produces currents up to 20-fold larger than homomers, with a reversal potential reflecting Na+-selective current, and co-purification from HEK293 cells confirms biochemical interaction. Heteromeric ASIC2a/3 channels show increased sensitivity to Gd3+ (IC50 ~40 µM) compared to ASIC2a homomers (IC50 ≥1 mM).\",\n      \"method\": \"Xenopus oocyte co-expression electrophysiology, co-purification/co-immunoprecipitation from HEK293 cells, in situ hybridization for co-localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reconstitution in oocytes plus biochemical co-purification, multiple orthogonal methods\",\n      \"pmids\": [\"10842183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"DRASIC (ASIC3) contributes to the composition and properties of H+-gated currents in large-diameter DRG neurons: genetic disruption of DRASIC slows desensitization kinetics, decreases pH sensitivity, increases amiloride sensitivity, and alters FMRF-related peptide potentiation, indicating DRASIC forms heteromultimeric acid-activated channels with other DEG/ENaC subunits in these neurons.\",\n      \"method\": \"Whole-cell patch clamp on large DRG neurons from DRASIC-/− mice vs. wild-type\",\n      \"journal\": \"Journal of neurophysiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined electrophysiological phenotype, multiple current properties measured\",\n      \"pmids\": [\"12037186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"APETx2, a 42-amino-acid peptide from sea anemone Anthopleura elegantissima, acts at the extracellular face of ASIC3 to reversibly inhibit rat ASIC3 homomeric channels (IC50 = 63 nM) and ASIC3-containing heteromeric channels, without affecting ASIC1a, ASIC1b, or ASIC2a. It does not change unitary conductance. It also inhibits the native ASIC3-like current in rat DRG neurons (IC50 = 216 nM).\",\n      \"method\": \"Electrophysiology in heterologous expression systems (Xenopus oocytes, HEK cells) and primary DRG neuron patch clamp; pharmacological characterization with outside-out patches\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct pharmacological characterization with multiple expression systems and native neurons, rigorous controls\",\n      \"pmids\": [\"15044953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ASIC3 is regulated by protein kinase C (PKC) through its interaction with the silent ASIC2b subunit and the PDZ scaffold protein PICK-1. PKC stimulation (via phorbol ester PDBu or serotonin) increases native ASIC3-like currents in DRG neurons and shifts pH dependence toward more physiological values only in heteromeric ASIC3/ASIC2b channels (not ASIC3 homomers), requiring PICK-1 which binds the ASIC2b C-terminus.\",\n      \"method\": \"Whole-cell patch clamp of rat DRG neurons and heterologous expression, pharmacological PKC activation, PICK-1 interaction identified by PDZ domain analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patch clamp in native neurons and heterologous system, multiple orthogonal approaches in one study, clear molecular dissection\",\n      \"pmids\": [\"14976185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ASIC2 and ASIC3 null mutations do not alter mechanically activated currents (amplitude or kinetics) in isolated DRG neuron cell bodies, indicating that ASIC2 and ASIC3 are not required for mechanotransduction at the cell body level.\",\n      \"method\": \"Whole-cell patch clamp of cultured DRG neurons from ASIC2-/−, ASIC3-/−, and double-KO mice with mechanical stimulation\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO electrophysiology, explicit negative result replicated across multiple genotypes\",\n      \"pmids\": [\"14990679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ASIC3 produces a sustained inward current within the pH range (7.3–6.7) that occurs during cardiac/skeletal muscle ischemia, because activation and inactivation curves overlap in this range. This sustained mode does not occur with ASIC1a homomers or ASIC1a/3 heteromers; ASIC2a/3 heteromers produce larger sustained currents than ASIC3 homomers. Lactate shifts activation to more basic pH; amiloride paradoxically increases ASIC3 current at pH 7.0. Cardiac sensory neurons exhibit a small perfectly sustained current at pH 7.0–7.4 that is potentiated by Zn2+ and amiloride.\",\n      \"method\": \"Patch clamp on transfected cell lines and fluorescently tagged cardiac sensory neurons; pH dose-response curves; pharmacological modulators\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstitution with pharmacological validation and native neuron recordings, multiple orthogonal approaches\",\n      \"pmids\": [\"16873722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ASIC3 in primary afferent fibers innervating muscle (not skin) is required for development of cutaneous mechanical hyperalgesia after carrageenan-induced muscle inflammation. Rescue of the phenotype by herpes virus-mediated ASIC3 expression specifically in muscle (not skin) of ASIC3-/− mice restores mechanical hyperalgesia, establishing peripheral muscle ASIC3 as the critical locus.\",\n      \"method\": \"ASIC3-/− mice, behavioral pain testing (mechanical and heat), herpes virus vector-mediated tissue-specific ASIC3 re-expression, DRG mRNA/protein confirmation\",\n      \"journal\": \"Pain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO plus tissue-specific genetic rescue experiment, multiple behavioral modalities\",\n      \"pmids\": [\"17134831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PSD-95 interacts with ASIC3 via its PDZ domain and reduces ASIC3 cell surface expression and H+-gated current. ASIC3 and PSD-95 co-immunoprecipitate within lipid raft (detergent-resistant membrane) fractions; disruption of lipid rafts with methyl-β-cyclodextrin abolishes PSD-95 inhibition of ASIC3. Mutation of palmitoylation sites (Cys residues) in PSD-95 prevents its targeting to lipid rafts and its inhibition of ASIC3. Cell surface ASIC3 is enriched in lipid raft fractions.\",\n      \"method\": \"Co-immunoprecipitation, detergent-resistant membrane fractionation, methyl-β-cyclodextrin cholesterol depletion, site-directed mutagenesis of PSD-95 palmitoylation sites, whole-cell patch clamp\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (Co-IP, fractionation, mutagenesis, electrophysiology) in one study\",\n      \"pmids\": [\"18579798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SMAD3 acts as a transcriptional repressor of the ASIC3 gene in nucleus pulposus cells. TGF-β treatment decreases ASIC3 mRNA/protein; constitutively active ALK5 or SMAD3 suppresses ASIC3 promoter activity; dominant-negative SMAD3 or SMAD7 restores it. SMAD3 directly binds two CAGA box motifs in the rat ASIC3 promoter as shown by gel-shift, supershift, and chromatin immunoprecipitation assays. Suppression requires histone deacetylase recruitment.\",\n      \"method\": \"Luciferase reporter assays, dominant-negative/constitutively active constructs, EMSA/supershift, ChIP, smad3-null cell rescue\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (reporter assay, EMSA, ChIP, null cell rescue) in one rigorous study\",\n      \"pmids\": [\"18466073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"p75NTR and ERK signaling maintain basal ASIC3 expression in nucleus pulposus cells: blocking p75NTR suppresses basal ASIC3 promoter activity; dominant-negative MEK suppresses, while constitutively active MEK1 increases, ASIC3 promoter activity. ASIC3 promotes disc cell survival under acidic and hyperosmotic conditions by lowering caspase-3 activity.\",\n      \"method\": \"Luciferase reporter assays, dominant-negative/constitutively active MEK, p75NTR blocking antibody/dominant-negative construct, MTT and caspase-3 activity assays\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple reporter and pharmacological approaches in single lab study\",\n      \"pmids\": [\"17696763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ASIC2a and ASIC3 are the major ASIC subunits forming heteromers in cardiac dorsal root ganglia neurons. Patch-clamp studies in cardiac afferents from ASIC3-/− mice show currents matching ASIC2a homomers; ASIC2-/− cardiac afferents show currents matching ASIC3 channels. Current properties of wild-type cardiac DRG neurons most closely match ASIC2a/3 heteromeric channels.\",\n      \"method\": \"Retrograde labeling + patch clamp in cardiac afferents from ASIC-null mice; pharmacological and kinetic characterization\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic ablation in native neurons with multiple ASIC-null genotypes, functional characterization\",\n      \"pmids\": [\"19590043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ASIC1a, ASIC2a, and ASIC3 form heteromeric channels as the principal ASICs in skeletal muscle afferents. ASIC1a-/− currents show reduced pH sensitivity and faster recovery; ASIC2-/− currents show diminished Zn2+ potentiation; ASIC3-/− currents show slower desensitization. ASIC-like currents are absent in triple-null (ASIC1a/2a/3) mice.\",\n      \"method\": \"Patch clamp of isolated labeled mouse muscle afferents from specific ASIC-/− mice; pharmacological modulation\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic genetic dissection with multiple single and triple KO mice, patch clamp in native neurons\",\n      \"pmids\": [\"23109675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Simultaneous knockout of ASIC1a, ASIC2, and ASIC3 (triple-KO) increases cutaneous mechanosensitivity: triple-KO mice show increased paw withdrawal frequency to von Frey filaments and enhanced single-fiber A-mechanonociceptor responses compared to wild-type. Other fiber types are unaffected. This indicates ASIC subunits influence mechanosensitivity but likely do not directly transduce mechanical stimuli.\",\n      \"method\": \"Triple-KO behavioral testing (von Frey), single-fiber cutaneous nerve recordings\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic ablation with behavioral and electrophysiological phenotyping in single study\",\n      \"pmids\": [\"22506072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ASIC3 is expressed in parvalbumin-positive (Pv+) proprioceptor axons innervating muscle spindles. Conditional knockout of ASIC3 in Pv+ neurons disrupts spindle afferent sensitivity to dynamic stimuli and impairs mechanotransduction in Pv+ DRG neurons in response to substrate deformation-induced neurite stretching, but not direct neurite indentation. Global and Pv-Cre::Asic3f/f mice show similar deficits in grid and balance beam walking tasks.\",\n      \"method\": \"Asic3-KO/eGFPf-knockin mice, Cre-lox conditional KO, electrophysiology of muscle spindle afferents, localized elastic matrix mechanostimulation, behavioral tasks\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO, spindle afferent electrophysiology, cell-specific mechanostimulation, behavioral validation\",\n      \"pmids\": [\"27161260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ASIC3 in cerebrospinal fluid-contacting neurons of lamprey spinal cord mediates both mechanosensory and chemosensory (pH) responses. APETx2 (selective ASIC3 antagonist) blocks both mechanical stimulation-evoked and low-pH-evoked responses in these neurons. Lowering pH or applying somatostatin reduces locomotor burst rate; somatostatin receptor antagonist counteracts both effects.\",\n      \"method\": \"Whole-cell patch clamp of identified CSF-contacting neurons, APETx2 pharmacological blockade, imposed lateral bending, pH manipulation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct pharmacological blockade with APETx2 in native neurons with both mechanical and chemical stimuli\",\n      \"pmids\": [\"26743691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Sea anemone peptide Ugr 9-1 (π-AnmTX Ugr 9a-1) reversibly inhibits human ASIC3 expressed in Xenopus oocytes: it completely blocks the transient current component (IC50 10 µM) and partially inhibits the sustained component (IC50 1.44 µM). NMR spectroscopy revealed a novel 'boundless β-hairpin' structure stabilized by two disulfide bonds.\",\n      \"method\": \"Xenopus oocyte electrophysiology, NMR structure determination, in vivo pain assays in mice\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro electrophysiology plus NMR structural characterization in one study\",\n      \"pmids\": [\"23801332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ASIC3 and P2X3 receptors physically associate to form a multiprotein complex in sensory neurons. ASIC3 stimulation strongly inhibits P2X3R current partly through a Ca2+-dependent mechanism. The proton-binding site of ASIC3 is critical for this inhibitory effect. Co-immunoprecipitation and BN-PAGE/SDS-PAGE analysis are consistent with a heteromeric multiprotein structure (though not a single heteromeric channel). The two receptors switch their ionic permeabilities during activation.\",\n      \"method\": \"Patch clamp current measurements, co-immunoprecipitation, BN-PAGE, SDS-PAGE, Ca2+ chelation experiments, in vivo pain summation in rats\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, BN-PAGE, and electrophysiology as multiple orthogonal methods\",\n      \"pmids\": [\"29636447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RPRFamide (a 4-amino acid cono-RFamide from Conus textile venom) strongly potentiates ASIC3 currents and increases DRG neuron excitability. Injection into mouse gastrocnemius muscle enhances acid-induced muscle pain, and this enhancement is abolished by genetic inactivation of ASIC3.\",\n      \"method\": \"In vitro venom screen electrophysiology, patch clamp of isolated DRG neurons, ASIC3-/− mouse in vivo pain assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiology in native neurons plus genetic KO validation\",\n      \"pmids\": [\"28396446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ASIC1 and ASIC3 mediate acidity-induced epithelial-mesenchymal transition (EMT) in pancreatic cancer cells through a Ca2+/RhoA pathway. Acid-induced inward current via ASIC1/ASIC3 elevates intracellular Ca2+, which activates RhoA downstream; siRNA knockdown or pharmacological inhibition of ASIC1/ASIC3 decreases [Ca2+]i and RhoA, suppressing EMT. ASIC1/ASIC3 knockdown suppresses liver and lung metastasis in xenograft models.\",\n      \"method\": \"siRNA knockdown, pharmacological inhibition, Ca2+ imaging, RhoA assay, xenograft metastasis model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdown with multiple downstream pathway readouts and in vivo validation, single lab\",\n      \"pmids\": [\"28518134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ASIC3 mediates itch sensation via coincident detection of acidosis and nonproton ligands (SL-NH2). Co-administration of acid with SL-NH2 increases scratching in wild-type but not ASIC3-null mice. Mechanistically, SL-NH2 slows desensitization of proton-evoked currents by targeting the nonproton ligand-sensing domain in the extracellular region of ASIC3. ASIC3 gene ablation also reduces dry-skin-induced scratching.\",\n      \"method\": \"ASIC3-/− behavioral assay, patch clamp on primary sensory neurons, mutagenesis of nonproton ligand-sensing domain\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO behavioral phenotype plus electrophysiology with domain-level mechanistic dissection\",\n      \"pmids\": [\"26440887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PAR2 signaling sensitizes ASIC3 via an intracellular cascade involving G protein, PLC, PKC, and PKA. PAR2-activating peptide concentration-dependently increases ASIC3 currents in CHO cells expressing both ASIC3 and PAR2, increasing maximal response by ~59% without changing pH50. PAR2 activation also increases proton-evoked currents and spikes in rat DRG neurons. Inhibition of each signaling step (G protein, PLC, PKC, or PKA) abolishes PAR2-induced potentiation of ASIC3.\",\n      \"method\": \"Whole-cell patch clamp in CHO cells and DRG neurons, pharmacological inhibition of G protein/PLC/PKC/PKA\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic pharmacological dissection of signaling cascade in both heterologous and native cells\",\n      \"pmids\": [\"28754162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ASIC2a co-expression increases ASIC3 surface expression via heteromeric assembly, markedly enhancing the sustained component of proton-evoked currents. ASIC3 alone is largely retained in the ER; co-expression with ASIC2a drives plasma membrane targeting. Heteromeric association confirmed by BiFC assay.\",\n      \"method\": \"Surface biotinylation, bimolecular fluorescence complementation (BiFC), whole-cell patch clamp in heterologous cells\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BiFC plus electrophysiology in single lab, heterologous expression system\",\n      \"pmids\": [\"27241858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CAR (Coxsackievirus and adenovirus receptor) interacts with ASIC3 only when PSD-95 is co-expressed, and CAR recruits both PSD-95 and ASIC3 to cell-cell junctions. Furthermore, CAR rescues PSD-95-mediated inhibition of ASIC3 currents, indicating CAR can modulate ASIC3 trafficking through a PDZ-based scaffolding complex.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence localization, whole-cell patch clamp in heterologous cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, localization, and electrophysiology in heterologous cells, single lab\",\n      \"pmids\": [\"22809504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Amiloride exerts paradoxical potentiation of ASIC3 sustained currents at neutral pH while inhibiting currents at acidic pH. Mechanistically, amiloride causes alkaline shift of pH-dependent activation, inhibits steady-state desensitization (SSD), and requires extracellular Ca2+. Site-directed mutagenesis identifies E79 and E423 in the nonproton ligand-sensing domain as critical for amiloride-induced inhibition of SSD; disruption of the pore amiloride binding site (G445C) blunts both inhibition and potentiation.\",\n      \"method\": \"Whole-cell patch clamp, site-directed mutagenesis of ASIC3 expressed in heterologous cells\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution with systematic mutagenesis of multiple residues plus rigorous electrophysiological characterization\",\n      \"pmids\": [\"34721074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Multiscale MD simulations predict arachidonic acid (AA) binds the outer leaflet transmembrane region of ASIC3, with salt bridge interactions at R65 and R68 and aromatic interactions at Y58 in hASIC3. Subtle differences exist between ASIC1a and ASIC3 AA interaction patterns reversible by mutating three key residues at the outer TM1 leaflet. Longer, more unsaturated fatty acid tails show increased occupancy at this region.\",\n      \"method\": \"Multiscale molecular dynamics simulations, mutagenesis analysis in silico\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational prediction only, no experimental functional validation reported in this paper\",\n      \"pmids\": [\"36625864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-1β from ischemic muscle upregulates ASIC3 in single muscle afferent neurons (DRG), and nerve-specific knockdown of ASIC3 recapitulates the effects of inhibiting IL1β/IL1R signaling, reversing sensitization of group III/IV afferents and pain behaviors after ischemia-reperfusion injury. This establishes an IL1β → IL1R → ASIC3 signaling axis in muscle afferents mediating ischemic myalgia.\",\n      \"method\": \"In vitro IL-1β treatment of single DRG neurons, siRNA nerve-specific knockdown in vivo, afferent single-unit recordings, behavioral pain assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single-cell in vitro mechanism combined with nerve-specific KD and in vivo functional readouts\",\n      \"pmids\": [\"27358445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ASIC3 interacts with HIF-1α and ERK1/2 as shown by co-immunoprecipitation in nucleus pulposus cells. Hypoxia-induced ASIC3 upregulation is reduced by HIF-1α silencing, indicating mutual regulation. ASIC3 overexpression under hypoxia activates MAPK/ERK pathway, inhibits proliferation, arrests cell cycle in G1, and promotes apoptosis and autophagy; ASIC3 silencing reverses these effects.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown, ASIC3 overexpression, flow cytometry, western blot, CCK-8, transmission EM\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP for interaction, functional knockdown/OE with multiple cellular readouts, single lab\",\n      \"pmids\": [\"31202172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ASIC3 activation in nociceptors exacerbates psoriatic inflammation through a neurogenic pathway. Global or nociceptor-specific Asic3 KO in female mice alleviates imiquimod-induced psoriatic acanthosis and type 17 inflammation similarly to nociceptor ablation. Mechanistically, ASIC3 activation induces activity-dependent release of CGRP from sensory neurons to promote neurogenic inflammation; CGRP replenishment in skin of Asic3-KO mice restores the inflammatory response. Botulinum neurotoxin A and CGRP antagonists phenocopy Asic3 KO.\",\n      \"method\": \"Global and nociceptor-specific conditional KO, imiquimod-induced psoriasis model, CGRP rescue experiment, botulinum toxin, CGRP antagonists, histology\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO, mechanistic rescue with CGRP, pharmacological validation with multiple agents in one study\",\n      \"pmids\": [\"38902277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ASIC3 activation promotes M-CSF transcriptional regulation in macrophages, driving M2 polarization. M2 macrophages transduced by the ASIC3-M-CSF signal promote fibroblast-to-myofibroblast differentiation through TGF-β1, forming an ASIC3-M-CSF-TGF-β1 positive feedback loop in skin fibrosis.\",\n      \"method\": \"ASIC3 activation/inhibition in cultured cells, western blot, cytokine/macrophage polarization assays, fibroblast differentiation assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional cell biology with pathway dissection, single lab, primarily in vitro\",\n      \"pmids\": [\"35661105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"17β-estradiol (E2) upregulates ASIC3 protein expression in a dose- and time-dependent manner via estrogen receptor α (ERα); the ERα-specific antagonist MPP blocks this effect. Female rats have higher ASIC3 expression in DRG than males; ovariectomy decreases DRG ASIC3 expression; orchiectomy does not affect it.\",\n      \"method\": \"Co-transfection of ASIC3 and ERα in 293T cells with western blot, ERα antagonist MPP, in vivo ovariectomy/orchiectomy with DRG western blot\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — heterologous system with pharmacological blockade plus in vivo hormonal manipulation, single lab\",\n      \"pmids\": [\"30114476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ASIC3 expression is increased ~2-fold in knee joint afferents in rats with monoiodoacetate-induced osteoarthritis. Continuous intra-articular injection of APETx2 (ASIC3 blocker) inhibits weight-bearing pain, secondary hyperalgesia, and attenuates ASIC3 upregulation in joint afferents. Early APETx2 administration has chondroprotective effects.\",\n      \"method\": \"Immunohistochemistry, behavioral pain testing, intra-articular APETx2 injection, histology\",\n      \"journal\": \"Journal of biomedical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological block in vivo with behavioral and immunohistochemical readouts, single lab\",\n      \"pmids\": [\"22909215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ASIC3-like current in carotid body glomus cells mediates acidosis chemosensitivity. Increased ASIC3 expression in transgenic mice increases pH sensitivity while reducing cyanide/hypoxia sensitivity; ASIC3 deletion reduces pH sensitivity while increasing relative sensitivity to hypoxia. This reciprocal relationship demonstrates ASIC3 is a specific molecular determinant of acidosis chemotransduction in glomus cells.\",\n      \"method\": \"Ca2+ imaging in isolated glomus cells, ASIC3 transgenic and KO mice, pharmacological and hypoxia stimulation\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic gain and loss of function with functional Ca2+ measurements in native cells\",\n      \"pmids\": [\"23165770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ASIC3 is required for immediate exercise-induced pain (IEIP) but plays a protective role against muscle injury during strenuous exercise. ASIC3-/− mice do not develop reduced muscle withdrawal threshold immediately after exhaustive exercise (no IEIP). At 24 h, ASIC3-/− mice show lower locomotor activity, lower repeat exercise performance, and higher serum markers of muscle injury (LDH, CK) than wild-type mice.\",\n      \"method\": \"ASIC3-/− mice, treadmill exercise, muscle withdrawal threshold, locomotor testing, grip strength, serum enzyme assays\",\n      \"journal\": \"Frontiers in pain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with multiple functional outcome measures, single lab\",\n      \"pmids\": [\"37795390\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ASIC3 (also known as DRASIC, TNaC1, ACCN3) is a proton-gated, Na+-selective cation channel of the DEG/ENaC superfamily expressed predominantly in peripheral sensory neurons, where it functions as a sensitive detector of extracellular acidosis—including the mild, sustained pH drops (7.3–6.7) occurring during ischemia—by producing both transient and sustained inward currents; it forms heteromeric channels with ASIC2a and ASIC2b subunits (the latter requiring PICK-1 scaffold for PKC-dependent upregulation), is regulated at the plasma membrane by PSD-95 within lipid rafts, by CAR-mediated trafficking, and by estrogen receptor α-mediated transcriptional control; it acts via a Ca2+/RhoA pathway in non-neuronal cells and via CGRP release from nociceptors in neurogenic inflammation; it contributes to mechanosensory transduction in proprioceptors (muscle spindle dynamic sensitivity) and coincident detection of acid plus nonproton ligands to mediate itch; and its activity can be selectively blocked by APETx2 or potentiated by RPRFamide, cono-RFamides, and amiloride (paradoxically at neutral pH via the nonproton ligand-sensing domain).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ASIC3 is a proton-gated, Na+-selective cation channel of the DEG/ENaC superfamily that functions in peripheral sensory neurons as a detector of extracellular acidosis and contributes to nociception, mechanosensation, and chemosensation [#0, #2]. It distinctively produces a sustained inward current within the mild pH range (7.3–6.7) characteristic of cardiac and skeletal muscle ischemia, because its activation and inactivation curves overlap in this window; lactate, Zn2+, and amiloride further modulate this sustained mode [#6]. ASIC3 rarely acts as a homomer in vivo: it co-assembles into heteromeric channels with ASIC2a and ASIC2b that determine current amplitude, kinetics, pH sensitivity, and surface expression [#1, #11, #12, #22], and genetic dissection in cardiac and skeletal muscle afferents confirms ASIC2a/3 (and ASIC1a/2a/3) heteromers as the principal native channels [#11, #12]. Channel activity is tuned by intracellular scaffolds and kinases—PICK-1 enables PKC-dependent potentiation of ASIC3/ASIC2b channels, PSD-95 within lipid rafts reduces surface expression and current, and CAR modulates trafficking through this PDZ-based complex [#4, #8, #23]—and is further sensitized by PAR2 signaling through a G protein/PLC/PKC/PKA cascade [#21]. In sensory physiology, muscle ASIC3 drives inflammatory mechanical hyperalgesia and ischemic myalgia via an IL-1β→IL-1R axis [#7, #26], contributes to proprioceptor and muscle-spindle dynamic sensitivity [#14], mediates immediate exercise-induced pain while protecting against muscle injury [#33], and mediates acid-plus-nonproton-ligand coincident detection underlying itch [#20]. Beyond neurons, ASIC3 acts via Ca2+/RhoA signaling in pancreatic cancer EMT and metastasis [#19] and drives CGRP-dependent neurogenic inflammation in psoriasis [#28]. ASIC3 expression is transcriptionally controlled by SMAD3 repression, p75NTR/ERK maintenance, and estrogen-receptor-α induction [#9, #10, #30]. Pharmacologically, the sea anemone peptide APETx2 selectively inhibits ASIC3, RFamide peptides potentiate it, and amiloride paradoxically potentiates the sustained current at neutral pH through the nonproton ligand-sensing domain [#3, #18, #24].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established that ASIC3 is not an obligate homomer but co-assembles with ASIC2a into proton-gated heteromers, answering how subunit composition sets channel properties.\",\n      \"evidence\": \"Xenopus oocyte co-expression electrophysiology plus co-purification from HEK293 cells\",\n      \"pmids\": [\"10842183\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the heteromer not resolved\", \"Did not establish native composition in sensory neurons\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined ASIC3's in vivo sensory role by showing its loss bidirectionally alters mechanoreceptor and acid/heat nociceptor sensitivity, implicating it in heteromeric channels in sensory endings.\",\n      \"evidence\": \"DRASIC-/- knockout mouse with skin immunolocalization and single-fiber recordings\",\n      \"pmids\": [\"11754838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the specific heteromeric partners in each fiber type\", \"Mechanism of mechanoreceptor modulation unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed ASIC3 shapes the kinetics, pH sensitivity, and pharmacology of native DRG H+-gated currents, confirming it forms heteromultimeric acid-sensors in sensory neurons.\",\n      \"evidence\": \"Whole-cell patch clamp of large DRG neurons from DRASIC-/- vs wild-type mice\",\n      \"pmids\": [\"12037186\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Partner subunits in large DRG neurons not biochemically defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified APETx2 as a selective ASIC3 antagonist, providing the key pharmacological tool to probe native ASIC3 currents.\",\n      \"evidence\": \"Electrophysiology in oocytes, HEK cells, and rat DRG neurons with outside-out patches\",\n      \"pmids\": [\"15044953\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding site on ASIC3 not mapped\", \"Cross-reactivity in mixed heteromers incompletely characterized\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolved how kinase signaling tunes ASIC3 by showing PKC potentiates ASIC3/ASIC2b channels via the PICK-1 scaffold binding the ASIC2b C-terminus.\",\n      \"evidence\": \"Patch clamp of DRG and heterologous cells with PKC activation and PDZ-domain interaction analysis\",\n      \"pmids\": [\"14976185\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphorylation site on the channel not identified\", \"Whether PKC acts directly on ASIC3 or via PICK-1 unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Distinguished cell-body mechanotransduction from sensory-ending function by showing ASIC2/ASIC3 are dispensable for mechanically activated currents in DRG somata.\",\n      \"evidence\": \"Patch clamp of cultured DRG neurons from single and double KO mice with mechanical stimulation\",\n      \"pmids\": [\"14990679\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Negative result does not exclude a role at peripheral endings\", \"Possible compensation by other channels not addressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Explained ASIC3's ischemia-sensing capacity by demonstrating a sustained current in the mild pH range where activation and inactivation overlap, enhanced in ASIC2a/3 heteromers.\",\n      \"evidence\": \"Patch clamp of transfected lines and cardiac sensory neurons with pH dose-response and pharmacology\",\n      \"pmids\": [\"16873722\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of overlapping activation/inactivation curves not structurally defined\", \"Contribution of endogenous lactate in vivo not quantified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Localized the critical site of inflammatory mechanical hyperalgesia to muscle ASIC3 using tissue-specific genetic rescue.\",\n      \"evidence\": \"ASIC3-/- mice with herpesvirus-mediated muscle-specific re-expression and behavioral testing\",\n      \"pmids\": [\"17134831\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream central sensitization mechanism not defined\", \"Did not identify the proton/inflammatory trigger in muscle\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Linked ASIC3 expression and cell survival in nucleus pulposus to p75NTR/ERK signaling, extending ASIC3 function beyond neurons.\",\n      \"evidence\": \"Luciferase reporters, dominant-negative/constitutively active MEK, p75NTR blockade, caspase-3 assays\",\n      \"pmids\": [\"17696763\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab reporter-based study\", \"Direct transcription factor binding not shown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Established transcriptional repression of ASIC3 by SMAD3 downstream of TGF-β, defining a direct promoter-level control mechanism.\",\n      \"evidence\": \"Reporter assays, EMSA/supershift, ChIP, and smad3-null cell rescue in nucleus pulposus cells\",\n      \"pmids\": [\"18466073\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relevance to neuronal ASIC3 regulation not tested\", \"HDAC partner identity not specified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed PSD-95 within lipid rafts is a negative regulator of ASIC3 surface expression and current, revealing membrane-microdomain control.\",\n      \"evidence\": \"Co-IP, detergent-resistant membrane fractionation, cholesterol depletion, PSD-95 palmitoylation mutagenesis, patch clamp\",\n      \"pmids\": [\"18579798\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance in sensory neurons not established\", \"Mechanism by which raft localization reduces current unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined the major native cardiac afferent ASIC as the ASIC2a/3 heteromer using complementary genetic ablations.\",\n      \"evidence\": \"Retrograde labeling and patch clamp in cardiac afferents from ASIC2-/- and ASIC3-/- mice\",\n      \"pmids\": [\"19590043\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Heteromer stoichiometry not determined\", \"Contribution to cardiac pain perception in vivo not directly measured here\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified ASIC3 as a specific molecular determinant of acidosis chemotransduction in carotid body glomus cells via reciprocal gain/loss of function.\",\n      \"evidence\": \"Ca2+ imaging in glomus cells from ASIC3 transgenic and KO mice with pH and hypoxia stimulation\",\n      \"pmids\": [\"23165770\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Heteromeric partners in glomus cells not defined\", \"Link to ventilatory output not directly tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated ASIC1a/2a/3 heteromers are the principal acid sensors of skeletal muscle afferents through systematic single and triple knockouts.\",\n      \"evidence\": \"Patch clamp of labeled muscle afferents from multiple ASIC-null genotypes\",\n      \"pmids\": [\"23109675\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Subunit ratio within native heteromers unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Clarified that ASIC subunits influence but do not directly transduce cutaneous mechanical stimuli, since triple-KO increases mechanosensitivity.\",\n      \"evidence\": \"Triple-KO von Frey behavior and single-fiber cutaneous recordings\",\n      \"pmids\": [\"22506072\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the actual mechanotransducer remains open\", \"Mechanism of the modulatory effect unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed CAR recruits ASIC3 and PSD-95 to cell-cell junctions and can rescue PSD-95-mediated inhibition, adding a trafficking layer to the PDZ scaffold network.\",\n      \"evidence\": \"Co-IP, immunofluorescence, and patch clamp in heterologous cells\",\n      \"pmids\": [\"22809504\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Heterologous system only\", \"Physiological context in sensory neurons untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Provided in vivo evidence for ASIC3 in osteoarthritic joint pain and a candidate chondroprotective role using APETx2 blockade.\",\n      \"evidence\": \"Immunohistochemistry, behavioral pain testing, and intra-articular APETx2 in a monoiodoacetate OA model\",\n      \"pmids\": [\"22909215\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab pharmacology\", \"Cellular mechanism of chondroprotection unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Characterized Ugr 9-1 as a structurally novel ASIC3 inhibitor that differentially blocks transient versus sustained current components.\",\n      \"evidence\": \"Xenopus oocyte electrophysiology, NMR structure, and mouse pain assays\",\n      \"pmids\": [\"23801332\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding site on ASIC3 not mapped\", \"Selectivity across heteromers not fully tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed ASIC3 mediates itch via coincident detection of acid and the nonproton ligand SL-NH2 acting on an extracellular ligand-sensing domain.\",\n      \"evidence\": \"ASIC3-/- scratching behavior, patch clamp, and nonproton ligand-sensing domain mutagenesis\",\n      \"pmids\": [\"26440887\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous nonproton ligand in itch not identified\", \"Downstream itch circuitry not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established muscle ASIC3 as a node in an IL-1β→IL-1R axis driving ischemic myalgia through afferent sensitization.\",\n      \"evidence\": \"IL-1β treatment of single DRG neurons, nerve-specific siRNA knockdown, single-unit recordings, behavior\",\n      \"pmids\": [\"27358445\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional mechanism of IL-1β-induced ASIC3 upregulation not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined ASIC3 in proprioceptor axons as a contributor to muscle-spindle dynamic sensitivity and stretch-dependent mechanotransduction.\",\n      \"evidence\": \"Asic3 conditional KO in Pv+ neurons, spindle afferent electrophysiology, elastic-matrix stimulation, behavior\",\n      \"pmids\": [\"27161260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ASIC3 directly transduces stretch or modulates a transducer unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated dual mechano- and chemosensory ASIC3 function in lamprey CSF-contacting neurons using APETx2 blockade.\",\n      \"evidence\": \"Patch clamp of identified CSF-contacting neurons with APETx2, mechanical bending, and pH manipulation\",\n      \"pmids\": [\"26743691\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of mechanical gating in these neurons not defined\", \"Conservation to mammalian CSF-contacting neurons not shown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed ASIC2a co-expression rescues ASIC3 from ER retention, driving surface targeting and enhancing the sustained current.\",\n      \"evidence\": \"Surface biotinylation, BiFC, and patch clamp in heterologous cells\",\n      \"pmids\": [\"27241858\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Heterologous system only\", \"ER retention signal on ASIC3 not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified a physical and functional ASIC3–P2X3 complex in which ASIC3 activation inhibits P2X3 current via a Ca2+-dependent mechanism.\",\n      \"evidence\": \"Patch clamp, reciprocal Co-IP, BN-PAGE/SDS-PAGE, Ca2+ chelation, in vivo pain summation\",\n      \"pmids\": [\"29636447\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the complex unresolved\", \"Not a single heteromeric channel; interface undefined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Characterized the cono-RFamide RPRFamide as a potentiator of ASIC3 that enhances acid-induced muscle pain in an ASIC3-dependent manner.\",\n      \"evidence\": \"Venom electrophysiology, DRG patch clamp, and ASIC3-/- in vivo pain assay\",\n      \"pmids\": [\"28396446\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding site for RFamide peptides not mapped\", \"Endogenous mammalian RFamide relevance not addressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined PAR2 as a sensitizer of ASIC3 acting through a G protein/PLC/PKC/PKA cascade in heterologous and native neurons.\",\n      \"evidence\": \"Patch clamp in CHO cells and DRG neurons with stepwise pharmacological inhibition\",\n      \"pmids\": [\"28754162\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct phosphorylation target on ASIC3 not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended ASIC3 function to cancer biology, showing ASIC1/ASIC3 mediate acidity-induced EMT and metastasis via a Ca2+/RhoA pathway.\",\n      \"evidence\": \"siRNA knockdown, pharmacological inhibition, Ca2+ imaging, RhoA assay, xenograft metastasis\",\n      \"pmids\": [\"28518134\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Relative contribution of ASIC1 vs ASIC3 not dissected\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected ASIC3 to sex-dependent expression by showing estrogen-receptor-α-mediated upregulation of ASIC3 protein.\",\n      \"evidence\": \"Co-transfection western blot with ERα antagonist and in vivo ovariectomy/orchiectomy\",\n      \"pmids\": [\"30114476\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ERα acts at the ASIC3 promoter directly not shown\", \"Functional consequence for pain not measured here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Implicated ASIC3 in hypoxic nucleus pulposus cell fate through interaction with HIF-1α and ERK1/2 and downstream MAPK/ERK-driven apoptosis and autophagy.\",\n      \"evidence\": \"Co-IP, shRNA knockdown, overexpression, flow cytometry, western blot, EM\",\n      \"pmids\": [\"31202172\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab correlative interaction data\", \"Direct vs indirect HIF-1α interaction unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mechanistically dissected amiloride's paradoxical potentiation of ASIC3 sustained current at neutral pH, mapping it to nonproton ligand-sensing residues E79/E423 and the pore site G445.\",\n      \"evidence\": \"Patch clamp with systematic site-directed mutagenesis in heterologous cells\",\n      \"pmids\": [\"34721074\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural model of dual amiloride action not resolved\", \"Physiological relevance of neutral-pH potentiation untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Implicated ASIC3 in skin fibrosis through an ASIC3–M-CSF–TGF-β1 positive feedback loop driving M2 macrophage polarization and myofibroblast differentiation.\",\n      \"evidence\": \"ASIC3 activation/inhibition in cultured cells, macrophage polarization and fibroblast differentiation assays\",\n      \"pmids\": [\"35661105\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Primarily in vitro\", \"How acid activation occurs in fibrotic tissue not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a dual role for ASIC3 in exercise: required for immediate exercise-induced pain but protective against strenuous-exercise muscle injury.\",\n      \"evidence\": \"ASIC3-/- mice with treadmill exercise, withdrawal threshold, locomotor and grip testing, serum injury markers\",\n      \"pmids\": [\"37795390\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of protection against muscle injury not defined\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Predicted a transmembrane arachidonic-acid binding site on ASIC3 involving R65, R68, and Y58, proposing lipid modulation of the channel.\",\n      \"evidence\": \"Multiscale molecular dynamics simulations with in silico mutagenesis\",\n      \"pmids\": [\"36625864\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Computational prediction without experimental functional validation\", \"Functional effect of AA binding on ASIC3 not measured\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established ASIC3 as a driver of neurogenic psoriatic inflammation through activity-dependent CGRP release from nociceptors.\",\n      \"evidence\": \"Global and nociceptor-specific conditional KO, imiquimod psoriasis model, CGRP rescue, botulinum toxin, CGRP antagonists\",\n      \"pmids\": [\"38902277\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous acidic/ligand trigger in psoriatic skin not defined\", \"Sex-specificity of the effect not fully explained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A high-resolution structural basis for ASIC3's overlapping activation/inactivation, heteromer interfaces, and the nonproton ligand-sensing domain that integrates protons, RFamides, and amiloride remains undefined.\",\n      \"evidence\": \"No structural study in the timeline resolves the full-length channel or its modulator binding sites\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No experimental structure of ASIC3 or its heteromers\", \"Subunit stoichiometry of native heteromers unresolved\", \"Direct phosphorylation sites mediating kinase potentiation unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005216\", \"supporting_discovery_ids\": [1, 6, 2]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [20, 24, 6]},\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [1, 6, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [8, 22, 23]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 2, 6]},\n      {\"term_id\": \"R-HSA-9709957\", \"supporting_discovery_ids\": [20, 32, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 21, 19]}\n    ],\n    \"complexes\": [\n      \"ASIC2a/ASIC3 heteromeric channel\",\n      \"ASIC1a/ASIC2a/ASIC3 heteromeric channel\",\n      \"ASIC3/ASIC2b/PICK-1 complex\",\n      \"ASIC3–P2X3 multiprotein complex\"\n    ],\n    \"partners\": [\n      \"ASIC2a\",\n      \"ASIC2b\",\n      \"ASIC1a\",\n      \"PICK1\",\n      \"DLG4\",\n      \"CXADR\",\n      \"P2RX3\",\n      \"HIF1A\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}