| 2001 |
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. |
Gene knockout mouse (DRASIC-/−), immunolocalization in skin nerve endings, single-fiber electrophysiology |
Neuron |
High |
11754838
|
| 2000 |
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). |
Xenopus oocyte co-expression electrophysiology, co-purification/co-immunoprecipitation from HEK293 cells, in situ hybridization for co-localization |
The Journal of biological chemistry |
High |
10842183
|
| 2002 |
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. |
Whole-cell patch clamp on large DRG neurons from DRASIC-/− mice vs. wild-type |
Journal of neurophysiology |
High |
12037186
|
| 2004 |
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). |
Electrophysiology in heterologous expression systems (Xenopus oocytes, HEK cells) and primary DRG neuron patch clamp; pharmacological characterization with outside-out patches |
The EMBO journal |
High |
15044953
|
| 2004 |
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. |
Whole-cell patch clamp of rat DRG neurons and heterologous expression, pharmacological PKC activation, PICK-1 interaction identified by PDZ domain analysis |
The Journal of biological chemistry |
High |
14976185
|
| 2004 |
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. |
Whole-cell patch clamp of cultured DRG neurons from ASIC2-/−, ASIC3-/−, and double-KO mice with mechanical stimulation |
The Journal of physiology |
High |
14990679
|
| 2006 |
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. |
Patch clamp on transfected cell lines and fluorescently tagged cardiac sensory neurons; pH dose-response curves; pharmacological modulators |
Circulation research |
High |
16873722
|
| 2006 |
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. |
ASIC3-/− mice, behavioral pain testing (mechanical and heat), herpes virus vector-mediated tissue-specific ASIC3 re-expression, DRG mRNA/protein confirmation |
Pain |
High |
17134831
|
| 2008 |
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. |
Co-immunoprecipitation, detergent-resistant membrane fractionation, methyl-β-cyclodextrin cholesterol depletion, site-directed mutagenesis of PSD-95 palmitoylation sites, whole-cell patch clamp |
American journal of physiology. Cell physiology |
High |
18579798
|
| 2008 |
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. |
Luciferase reporter assays, dominant-negative/constitutively active constructs, EMSA/supershift, ChIP, smad3-null cell rescue |
Journal of bone and mineral research |
High |
18466073
|
| 2007 |
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. |
Luciferase reporter assays, dominant-negative/constitutively active MEK, p75NTR blocking antibody/dominant-negative construct, MTT and caspase-3 activity assays |
Journal of bone and mineral research |
Medium |
17696763
|
| 2009 |
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. |
Retrograde labeling + patch clamp in cardiac afferents from ASIC-null mice; pharmacological and kinetic characterization |
Circulation research |
High |
19590043
|
| 2012 |
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. |
Patch clamp of isolated labeled mouse muscle afferents from specific ASIC-/− mice; pharmacological modulation |
FASEB journal |
High |
23109675
|
| 2012 |
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. |
Triple-KO behavioral testing (von Frey), single-fiber cutaneous nerve recordings |
PloS one |
High |
22506072
|
| 2016 |
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. |
Asic3-KO/eGFPf-knockin mice, Cre-lox conditional KO, electrophysiology of muscle spindle afferents, localized elastic matrix mechanostimulation, behavioral tasks |
Nature communications |
High |
27161260
|
| 2016 |
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. |
Whole-cell patch clamp of identified CSF-contacting neurons, APETx2 pharmacological blockade, imposed lateral bending, pH manipulation |
Nature communications |
High |
26743691
|
| 2013 |
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. |
Xenopus oocyte electrophysiology, NMR structure determination, in vivo pain assays in mice |
The Journal of biological chemistry |
High |
23801332
|
| 2017 |
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. |
Patch clamp current measurements, co-immunoprecipitation, BN-PAGE, SDS-PAGE, Ca2+ chelation experiments, in vivo pain summation in rats |
Nature communications |
High |
29636447
|
| 2017 |
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. |
In vitro venom screen electrophysiology, patch clamp of isolated DRG neurons, ASIC3-/− mouse in vivo pain assay |
Proceedings of the National Academy of Sciences of the United States of America |
High |
28396446
|
| 2017 |
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. |
siRNA knockdown, pharmacological inhibition, Ca2+ imaging, RhoA assay, xenograft metastasis model |
Cell death & disease |
Medium |
28518134
|
| 2015 |
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. |
ASIC3-/− behavioral assay, patch clamp on primary sensory neurons, mutagenesis of nonproton ligand-sensing domain |
Cell reports |
High |
26440887
|
| 2017 |
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. |
Whole-cell patch clamp in CHO cells and DRG neurons, pharmacological inhibition of G protein/PLC/PKC/PKA |
Journal of neuroinflammation |
High |
28754162
|
| 2016 |
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. |
Surface biotinylation, bimolecular fluorescence complementation (BiFC), whole-cell patch clamp in heterologous cells |
BMB reports |
Medium |
27241858
|
| 2012 |
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. |
Co-immunoprecipitation, immunofluorescence localization, whole-cell patch clamp in heterologous cells |
Biochemical and biophysical research communications |
Medium |
22809504
|
| 2021 |
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. |
Whole-cell patch clamp, site-directed mutagenesis of ASIC3 expressed in heterologous cells |
Frontiers in physiology |
High |
34721074
|
| 2023 |
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. |
Multiscale molecular dynamics simulations, mutagenesis analysis in silico |
The Journal of general physiology |
Low |
36625864
|
| 2016 |
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. |
In vitro IL-1β treatment of single DRG neurons, siRNA nerve-specific knockdown in vivo, afferent single-unit recordings, behavioral pain assays |
The Journal of neuroscience |
High |
27358445
|
| 2019 |
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. |
Co-immunoprecipitation, shRNA knockdown, ASIC3 overexpression, flow cytometry, western blot, CCK-8, transmission EM |
Biomedicine & pharmacotherapy |
Medium |
31202172
|
| 2024 |
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. |
Global and nociceptor-specific conditional KO, imiquimod-induced psoriasis model, CGRP rescue experiment, botulinum toxin, CGRP antagonists, histology |
Nature communications |
High |
38902277
|
| 2022 |
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. |
ASIC3 activation/inhibition in cultured cells, western blot, cytokine/macrophage polarization assays, fibroblast differentiation assay |
Cell death & disease |
Medium |
35661105
|
| 2008 |
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. |
Co-transfection of ASIC3 and ERα in 293T cells with western blot, ERα antagonist MPP, in vivo ovariectomy/orchiectomy with DRG western blot |
Neuroscience letters |
Medium |
30114476
|
| 2012 |
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. |
Immunohistochemistry, behavioral pain testing, intra-articular APETx2 injection, histology |
Journal of biomedical science |
Medium |
22909215
|
| 2010 |
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. |
Ca2+ imaging in isolated glomus cells, ASIC3 transgenic and KO mice, pharmacological and hypoxia stimulation |
The Journal of physiology |
High |
23165770
|
| 2023 |
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. |
ASIC3-/− mice, treadmill exercise, muscle withdrawal threshold, locomotor testing, grip strength, serum enzyme assays |
Frontiers in pain research |
Medium |
37795390
|