Affinage

ASIC2

Acid-sensing ion channel 2 · UniProt Q16515

Length
512 aa
Mass
57.7 kDa
Annotated
2026-06-09
59 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ASIC2 (MDEG/BNaC1) is a proton-gated, amiloride-sensitive cation channel of the DEG/ENaC superfamily whose ion-conducting activity, when constitutively activated by gain-of-function mutation, is directly cytotoxic (PMID:8631835). Proton gating depends on a set of protonatable residues in the extracellular loop, and mutating any one abolishes acid sensitivity without disrupting surface trafficking or heteromer formation (PMID:17881127); Na+ selectivity is set by a conserved lower-pore E18' acidic residue working together with ASIC2a-specific upper-pore residues E59/E62, distinguishing the basis of selectivity from ASIC1a (PMID:31952079). ASIC2 functions principally as a modulatory subunit that co-assembles into heteromeric channels with ASIC2b, ASIC3, and ASIC1a, with subunit composition dictating current amplitude, pH dependence, desensitization kinetics, and pharmacology (PMID:10842183, PMID:12736332, PMID:19590043, PMID:23109675); ASIC2a's first transmembrane domain and proximal post-TM1 region drive both its own membrane targeting and the surface delivery of partner subunits ASIC2b, ASIC3, and ASIC1a (PMID:27477936, PMID:27241858, PMID:26861816). Surface expression is held in check by C-terminal di-leucine motifs (PMID:26819004), by Hsc70-mediated ER retention (PMID:17878160), and by PSD-95 binding (PMID:24699665), while channel activity is dynamically tuned by PICK1-anchored PKC phosphorylation at Thr39 (PMID:11739374, PMID:12399460) and by AKAP150-anchored calcineurin dephosphorylation (PMID:17548344). Through these heteromers ASIC2 contributes to acid sensing in sensory afferents and the brain rather than acting as a direct mechanotransducer, since cutaneous mechanosensation, hearing, and somatic mechanically activated currents are intact or even enhanced in ASIC2-null animals (PMID:14990679, PMID:15169849, PMID:22506072). At the systems level ASIC2 is required for proprioceptive muscle spindle responses (PMID:36951012), modulates fear and aversive behaviors (PMID:24256442), supports myogenic vasoconstriction in cerebral and renal vessels jointly with βENaC (PMID:18296560, PMID:35285274), contributes to ischemic neuronal injury (PMID:26861816), and, via an albumin/ERK-induced truncated ASIC2b variant, mediates renal sodium retention in nephrotic syndrome (PMID:34166227). Hyperactivation drives Ca2+ overload and ROS that block proteasomal/autophagic degradation, producing p62/LC3-dependent aggregates and caspase-8 apoptosis (PMID:23239879).

Mechanistic history

Synthesis pass · year-by-year structured walk · 32 steps
  1. 1996 High

    Established that ASIC2/MDEG is an ion-conducting amiloride-sensitive cation channel and that its conductance itself can be cytotoxic, linking channel activity to neurodegeneration.

    Evidence Electrophysiology in Xenopus oocytes with gain-of-function mutagenesis and cell death assays

    PMID:8631835

    Open questions at the time
    • Did not establish physiological gating stimulus
    • Native subunit partners unknown
    • No structural basis for ion conduction
  2. 1997 Medium

    Defined ASIC2 as a brain-expressed member of a new DEG/ENaC branch co-expressed with a related subunit, raising the possibility of heteromeric channels.

    Evidence cDNA cloning, Northern blot, in situ hybridization, chromosomal mapping

    PMID:9037075

    Open questions at the time
    • Heteromultimerization proposed but not demonstrated
    • Functional channel properties not characterized
  3. 2000 High

    Showed that ASIC2 is a partner subunit whose co-assembly reshapes channel function, demonstrating direct heteromerization with ASIC3.

    Evidence Co-purification from HEK293 cells and oocyte electrophysiology

    PMID:10842183

    Open questions at the time
    • Stoichiometry of heteromer not resolved
    • Physiological context of ASIC2a/ASIC3 channels not established
  4. 2001 High

    Identified PICK1 as a direct PDZ-domain partner of the ASIC2 C-terminus that clusters the channel, providing a scaffold linking ASIC2 to regulatory machinery.

    Evidence Yeast two-hybrid, GST pull-down, co-IP, and immunohistochemistry in DRG and central neurons

    PMID:11739374

    Open questions at the time
    • Functional consequence of clustering not yet shown
    • Did not establish phosphorylation regulation
  5. 2002 High

    Connected the PICK1 scaffold to functional regulation, showing PKC potentiates ASIC2a current via direct phosphorylation at Thr39.

    Evidence Whole-cell patch clamp, 32P labeling, co-IP, and site-directed mutagenesis

    PMID:12399460

    Open questions at the time
    • Upstream signals activating PKC at the channel unknown
    • Did not address dephosphorylation
  6. 2003 High

    Demonstrated that the ASIC2b splice variant co-assembles with ASIC2a to produce channels with distinct extreme-acid responsiveness, expanding the functional repertoire from one gene.

    Evidence Native co-IP from taste tissue and oocyte electrophysiology

    PMID:12736332

    Open questions at the time
    • Trafficking determinants of the heteromer not defined
    • Physiological role in taste not established
  7. 2004 High

    Resolved whether ASIC2 is a direct somatic mechanotransducer; knockout neurons and mice retained normal mechanically activated currents and mechanosensation, arguing against a direct transducer role.

    Evidence Patch clamp of knockout DRG neurons and in vivo mechanosensation/auditory assays in ASIC2-/- mice

    PMID:14990679 PMID:15169849

    Open questions at the time
    • Did not exclude modulatory mechanosensory roles in specialized endings
    • Compensation by other ASICs not assessed
  8. 2005 Medium

    Showed ASIC2 expression in DRG neurons is maintained by BDNF, identifying a transcriptional/trophic input controlling channel abundance.

    Evidence Immunocytochemistry, RT-PCR, and pharmacological rescue in BDNF-deficient mouse DRG cultures

    PMID:15708491

    Open questions at the time
    • Direct signaling pathway from BDNF to ASIC2 transcription not defined
    • Functional channel consequence not measured
  9. 2006 Medium

    Revealed regulated intracellular retention of ASIC2 in glioma and that forced surface expression suppresses a constitutive Na+ conductance and tumor cell migration/growth, indicating negative regulation at the membrane.

    Evidence Patch clamp, migration assays, surface biotinylation, and chemical chaperone treatment

    PMID:16704974

    Open questions at the time
    • Identity of the retention machinery not yet defined here
    • Molecular basis of suppression of conductance unclear
  10. 2007 High

    Identified Hsc70 as the ER-retention factor for ASIC2 in glioma, mechanistically explaining intracellular sequestration and its link to migration.

    Evidence Co-IP, siRNA knockdown, electrophysiology, migration assay, and surface biotinylation

    PMID:17878160

    Open questions at the time
    • Whether Hsc70 retention is selective for specific ASIC2 conformers unknown
    • Generalizability beyond glioma not addressed here
  11. 2007 High

    Mapped the proton-sensing apparatus to five extracellular protonatable residues required for gating but dispensable for trafficking and heteromerization.

    Evidence Site-directed mutagenesis with surface trafficking imaging and patch clamp

    PMID:17881127

    Open questions at the time
    • Conformational mechanism coupling protonation to gating not resolved
    • No structural model
  12. 2007 High

    Defined a phosphatase arm of ASIC2 regulation, showing AKAP150 anchors calcineurin to tonically dephosphorylate and inhibit the channel, complementing PKC potentiation.

    Evidence GST pulldown, mass spec, co-IP, and pharmacological modulation in cortical neurons and CHO cells

    PMID:17548344

    Open questions at the time
    • Specific dephosphorylation site not mapped
    • Integration with PICK1/PKC at single channels unresolved
  13. 2008 Medium

    Extended Hsc70-dependent retention of ASIC2 to vascular smooth muscle, placing ASIC2 downstream of Hsc70 in controlling VSMC migration.

    Evidence siRNA knockdown with co-silencing epistasis and migration assays in VSMCs

    PMID:18310515

    Open questions at the time
    • Channel activity required for migration not directly demonstrated
    • Single-lab functional epistasis
  14. 2008 Medium

    Linked ASIC2 to vascular physiology, showing it is required for pressure-induced myogenic constriction of cerebral arteries.

    Evidence Pressure myography on cerebral arteries from ASIC2 knockout mice

    PMID:18296560

    Open questions at the time
    • Molecular partners in VSMC mechanosensing not identified here
    • Whether ASIC2 senses pressure directly unknown
  15. 2009 High

    Established native ASIC2a/ASIC3 heteromers as the predominant acid-sensing channels in cardiac afferents using genetic epistasis.

    Evidence Retrograde labeling and patch clamp across ASIC2-/-, ASIC3-/-, and double-KO mice

    PMID:19590043

    Open questions at the time
    • Functional role in cardiac afferent signaling in vivo not measured here
    • Stoichiometry not determined
  16. 2012 High

    Defined the subunit composition of muscle afferent ASICs as ASIC1a/ASIC2a/ASIC3 heteromers, with ASIC2 specifically conferring zinc potentiation.

    Evidence Patch clamp with pharmacological fingerprinting in muscle afferents from ASIC-null mice

    PMID:23109675

    Open questions at the time
    • Functional consequence of zinc potentiation in vivo unknown
  17. 2012 Medium

    Showed ASICs modulate rather than directly mediate cutaneous mechanotransduction, since triple knockout enhanced rather than abolished mechanonociceptor responses.

    Evidence von Frey assays and single-fiber recordings in triple ASIC knockout mice

    PMID:22506072

    Open questions at the time
    • Mechanism of modulation unresolved
    • ASIC2-specific contribution not isolated
  18. 2012 High

    Dissected the cytotoxic pathway of hyperactivated ASIC2, showing Ca2+/ROS-driven degradation blockade produces p62/LC3-dependent aggregates and caspase-8 apoptosis independent of Bax/Bak.

    Evidence Inducible G430F expression with calcium imaging, ROS measurement, apoptosis/caspase assays, and p62/LC3 siRNA

    PMID:23239879

    Open questions at the time
    • Relevance to physiological ASIC2 activation unclear
    • Trigger for aggregate formation not fully defined
  19. 2014 High

    Established ASIC2 as a brain channel that boosts ASIC1a surface expression and acid-evoked currents, with PSD-95 acting as a negative regulator of surface ASIC2a.

    Evidence Surface biotinylation, patch clamp in ASIC2-/- hippocampal neurons, co-IP, and PSD-95 overexpression

    PMID:24699665

    Open questions at the time
    • Mechanism by which PSD-95 reduces surface expression not defined
    • Interplay with PICK1 scaffolding unresolved
  20. 2016 Medium

    Showed ASIC2a is a chaperone-like trafficking subunit that delivers ASIC1a, ASIC3, and ASIC2b to the membrane, and identified its TM1/post-TM1 region as the membrane-targeting determinant.

    Evidence Surface biotinylation, BiFC, chimeric domain swaps, and electrophysiology in heterologous cells and neurons

    PMID:26861816 PMID:27241858 PMID:27477936

    Open questions at the time
    • Trafficking machinery engaged by TM1 not identified
    • Largely heterologous systems for ASIC3/ASIC2b
  21. 2016 High

    Identified two C-terminal di-leucine motifs as autonomous negative regulators of ASIC2a trafficking, surface density, dendritic targeting, and pH sensitivity.

    Evidence Mutagenesis with surface biotinylation, electrophysiology, and imaging in hippocampal slices

    PMID:26819004

    Open questions at the time
    • Adaptor proteins recognizing the di-leucine motifs not identified
  22. 2016 High

    Linked ASIC2 trafficking function to ischemic injury, showing ASIC2a facilitates ASIC1a surface delivery and that ASIC2 deletion protects brain regions from ischemic damage region-specifically.

    Evidence Patch clamp, biotinylation, organotypic slice injury, and in vivo MCAO stroke model in ASIC2-/- mice

    PMID:26861816

    Open questions at the time
    • Region-specificity mechanism unresolved
    • Relative contribution of ASIC2 vs ASIC1a to injury not separated
  23. 2017 Medium

    Connected ASIC2 to a downstream transcriptional program, showing acidosis-driven ASIC2 activates calcineurin/NFAT1 to promote colorectal cancer invasion.

    Evidence Overexpression/knockdown, invasion and metastasis models, calcineurin inhibition, and NFAT1 ChIP-seq

    PMID:28927426

    Open questions at the time
    • Direct coupling of channel conductance to calcineurin activation not demonstrated
    • Single-lab
  24. 2018 Medium

    Characterized dual modulation of ASIC1a/ASIC2a heteromers by PcTx1, inhibiting under desensitizing pH and potentiating at physiological pH by increasing proton affinity.

    Evidence Concentration-response patch clamp in CHO cells and cortical neurons

    PMID:29739981

    Open questions at the time
    • Toxin binding site on ASIC2a-containing heteromers not mapped
  25. 2019 High

    Identified three N-terminal ASIC2a residues (T25, T39, I40) that confer rapid resensitization, explaining a key kinetic difference from ASIC2b independent of internalization.

    Evidence Site-directed mutagenesis, domain-swap chimeras, patch clamp, and internalization assays

    PMID:31010811

    Open questions at the time
    • Structural mechanism of N-terminal control of gating unresolved
  26. 2019 Medium

    Identified the endogenous neuropeptide nocistatin as a direct proton-like agonist of ASIC2a, suggesting a non-proton activation ligand for ASICs.

    Evidence Oocyte electrophysiology with mambalgin-2 antagonist controls

    PMID:31443477

    Open questions at the time
    • Binding site and physiological relevance not established
    • Heterologous expression only
  27. 2020 High

    Resolved the molecular basis of ion selectivity in ASIC2a, showing conserved E18' plus ASIC2a-specific upper-pore E59/E62 govern Na+ preference differently from ASIC1a.

    Evidence Mutagenesis, electrophysiology, and molecular dynamics free-energy simulations

    PMID:31952079

    Open questions at the time
    • No experimental atomic structure of the ASIC2a pore
    • Selectivity in heteromers not addressed
  28. 2021 High

    Established a disease mechanism: an albumin/ERK-induced truncated ASIC2b variant co-assembling with ASIC2a mediates renal sodium retention in nephrotic syndrome.

    Evidence Oocyte electrophysiology, ASIC2b-null rat nephrotic model, and renal/ERK signaling analysis

    PMID:34166227

    Open questions at the time
    • Localization of the active channel along the nephron not fully defined
    • Direct channel activity in vivo not measured
  29. 2021 Medium

    Placed ASIC2 upstream of TRPV1 in baroreceptor mechanotransduction, showing the two form a complex and that ASIC2 inhibition blocks stretch-activated currents.

    Evidence Co-IP, biotin pull-down, cell-attached patch clamp in HEK293T, and aortic nerve recording

    PMID:34215968

    Open questions at the time
    • Whether ASIC2 directly senses stretch versus relays to TRPV1 unresolved
    • Includes heterologous reconstitution
  30. 2022 High

    Demonstrated functional partnership of ASIC2 and βENaC in vascular myogenic responses, with both jointly required for full renal afferent arteriolar constriction.

    Evidence Co-IP from VSMCs and pressure myography in single and double KO mice

    PMID:35285274

    Open questions at the time
    • Whether ASIC2/βENaC form a single channel complex not established
    • Mechanosensing mechanism unresolved
  31. 2023 Medium

    Established a physiological proprioceptive role, showing ASIC2 is required for muscle spindle stretch responses, motor coordination, and spinal alignment.

    Evidence In vivo proprioception tests, ex vivo muscle spindle electrophysiology, and skeletal analysis in Asic2 KO mice

    PMID:36951012

    Open questions at the time
    • Whether ASIC2 directly transduces spindle stretch versus modulates unresolved
  32. 2023 Medium

    Defined ASIC2A as the predominant nucleus accumbens subunit that integrates with ASIC1A and influences spine morphology and drug reward, though regional restoration alone is insufficient to rescue reward behavior.

    Evidence Western blot, AAV rescue, MSN patch clamp, conditioned place preference, and spine morphology in Asic2 KO mice

    PMID:36793786

    Open questions at the time
    • Circuit-level mechanism of reward modulation unresolved
    • Failure of regional rescue not explained

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ASIC2 transduces or modulates mechanical force across its diverse vascular, baroreceptor, and proprioceptive roles remains unresolved, as does an experimental atomic structure of ASIC2-containing channels and the adaptor machinery reading its trafficking motifs.
  • No atomic structure of ASIC2 channels
  • Direct mechanosensing mechanism undetermined
  • Trafficking adaptors for di-leucine motifs unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0060089 molecular transducer activity 3 GO:0140299 molecular sensor activity 2
Localization
GO:0005886 plasma membrane 5 GO:0005783 endoplasmic reticulum 3
Pathway
R-HSA-112316 Neuronal System 4 R-HSA-162582 Signal Transduction 3 R-HSA-382551 Transport of small molecules 3 R-HSA-5357801 Programmed Cell Death 1
Partners
AKAP5ASIC1AASIC2BASIC3DLG4HSPA8PICK1TRPV1
Complex memberships
ASIC1a/ASIC2a/ASIC3 heteromeric channelASIC2a/ASIC2b heteromeric channelASIC2a/ASIC3 heteromeric channel

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 MDEG (ASIC2) is an amiloride-sensitive cation channel permeable for Na+, K+, and Li+. Gain-of-function mutations homologous to those causing neurodegeneration in C. elegans constitutively activate the channel and cause cell death in mammalian cells, indicating the channel's ion-conducting activity underlies its cytotoxic effects. Electrophysiology (Xenopus oocyte expression), gain-of-function mutagenesis, cell death assays The Journal of biological chemistry High 8631835
1997 BNaC1 (ASIC2) and BNaC2 form a new branch of the DEG/ENaC superfamily. Both genes are co-expressed in most brain neurons throughout life, consistent with assembly into heteromultimeric channels. cDNA cloning, Northern blot, in situ hybridization, chromosomal mapping (17q11.2-12) Proceedings of the National Academy of Sciences of the United States of America Medium 9037075
2000 ASIC2a and ASIC3 subunits co-assemble into functional heteromeric proton-gated channels with greatly amplified acid-induced currents (up to 20-fold larger than homomers), a cation current selective for sodium, and increased sensitivity to gadolinium (IC50 ~40 µM vs. ≥1 mM for ASIC2a alone). Biochemical co-purification from HEK293 cells and Xenopus oocytes confirmed direct physical interaction. Xenopus oocyte electrophysiology, co-immunoprecipitation/co-purification from HEK293 cells The Journal of biological chemistry High 10842183
2001 PICK1 (a PDZ domain protein) interacts specifically with BNaC1/ASIC2 via the PDZ domain of PICK1 and the last four amino acids of ASIC2. Co-expression of both proteins leads to their clustering in intracellular compartments. PICK1 co-localizes with ASIC2 at peripheral mechanosensory nerve endings of DRG neurons and in dendrites of central neurons. Yeast two-hybrid screen, GST pull-down, co-immunoprecipitation, immunohistochemistry, subcellular localization imaging The Journal of biological chemistry High 11739374
2002 PKC potentiates ASIC2a current amplitude (~300%) when PICK1 is co-expressed, requiring both the PDZ domain of PICK1 and the PDZ-binding domain of ASIC2a. Direct PICK1-dependent phosphorylation of ASIC2a was demonstrated by 32P-labeling and immunoprecipitation; the major phosphorylation site was identified as Thr39 (TIR motif) in the N-terminus. PKC potentiation did not alter ASIC2a unitary conductance. Electrophysiology (whole-cell patch clamp), 32P phosphorylation labeling, co-immunoprecipitation, site-directed mutagenesis The Journal of biological chemistry High 12399460
2003 ASIC2b (an N-terminal splice variant of ASIC2a from the same gene) co-assembles with ASIC2a to form heteromeric channels in taste cells. The ASIC2a/ASIC2b heteromeric channel generates maximal inward currents at pH ≤2.0, and amiloride sensitivity is almost abolished at pH 2.0, distinguishing it from ASIC2a homomers. Co-immunoprecipitation from circumvallate papillae, Xenopus oocyte electrophysiology, immunohistochemistry The Journal of neuroscience High 12736332
2004 ASIC2 and ASIC3 null mutations do not alter mechanically activated current amplitude or kinetics in DRG neuron cell bodies, indicating that ASIC2 is not a direct transducer of mechanical stimuli at the soma level. Whole-cell patch clamp of cultured DRG neurons from ASIC2-/- and ASIC3-/- knockout mice The Journal of physiology High 14990679
2004 ASIC2 knockout mice show no impairment of cutaneous mechanosensation, visceral mechanonociception, or hearing, arguing against ASIC2 being an essential direct mechanotransducer in these modalities. Behavioral mechanosensation assays, auditory brainstem response, in vivo nerve recordings in ASIC2-/- mice The Journal of physiology High 15169849
2005 ASIC2 protein expression in medium/large DRG neurons is maintained by BDNF signaling: ASIC2 mRNA and protein are dramatically down-regulated in BDNF-deficient mice, and exogenous BDNF (10–100 ng/ml) rescues ASIC2 expression in a dose- and time-dependent manner that requires new transcription and protein synthesis. Immunocytochemistry, RT-PCR, pharmacological block of transcription/translation, BDNF-deficient mouse DRG cultures Neuroscience Medium 15708491
2006 ASIC2 is retained intracellularly in high-grade glioma cells; forcing its surface expression (via glycerol or sodium 4-phenylbutyrate) abolishes the constitutively active amiloride-sensitive inward Na+ current and reduces glioma cell growth and migration, indicating ASIC2 exerts negative regulation of this ENaC/DEG-mediated conductance when present at the plasma membrane. Electrophysiology (whole-cell patch clamp), cell migration assays, surface biotinylation, chemical chaperone treatment The Journal of biological chemistry Medium 16704974
2007 AKAP150 and the protein phosphatase calcineurin bind to ASIC2a (and ASIC1a) as demonstrated by pulldown and mass spectrometry followed by co-immunoprecipitation. Inhibiting PKA-AKAP150 interaction (Ht-31 peptide) reduces ASIC currents, while inhibiting calcineurin (cyclosporin A) increases ASIC currents, indicating that calcineurin-dependent dephosphorylation tonically inhibits ASIC2a activity. GST pulldown, mass spectrometry, co-immunoprecipitation, whole-cell patch clamp in cortical neurons and CHO cells, pharmacological inhibition The Journal of biological chemistry High 17548344
2007 Five specific protonatable residues in the extracellular loop of ASIC2a are required for proton-gated activation; mutating any one of these sites abolishes acid sensitivity while the channels still traffic normally to the cell surface and retain the capacity to form functional heteromers. Site-directed mutagenesis, immunocytochemistry (surface trafficking), whole-cell patch clamp electrophysiology Neuroscience letters High 17881127
2007 Hsc70 co-immunoprecipitates with ASIC2 and is overexpressed in glioma cells versus normal astrocytes. Hsc70 siRNA knockdown inhibits the constitutive amiloride-sensitive current, decreases glioma migration, and increases ASIC2 surface expression, demonstrating that Hsc70 retains ASIC2 in the ER of glioma cells. Co-immunoprecipitation, siRNA knockdown, electrophysiology, cell migration assay, surface biotinylation The Journal of biological chemistry High 17878160
2008 Hsc70 inhibits ASIC2 surface expression in vascular smooth muscle cells (VSMCs). Hsc70 silencing increases ASIC2 cell surface expression and inhibits VSMC migration; co-silencing of ASIC2 abolishes this effect, placing ASIC2 downstream of Hsc70 in regulating VSMC migration. siRNA knockdown, surface expression assay, VSMC migration (chemotaxis) assay American journal of physiology. Heart and circulatory physiology Medium 18310515
2008 Pressure-induced (myogenic) constriction in mouse middle cerebral arteries is impaired in ASIC2-/- and ASIC2+/- mice, while constriction to KCl and phenylephrine is unaffected, demonstrating that normal ASIC2 expression is required for the myogenic response in cerebral arteries. Pressure myography on isolated middle cerebral arteries from ASIC2 knockout mice American journal of physiology. Heart and circulatory physiology Medium 18296560
2009 ASIC2a and ASIC3 are the principal ASIC subunits in cardiac dorsal root ganglia afferents. In ASIC3-/- cardiac afferents, currents match ASIC2a homomeric properties; in ASIC2-/- afferents, currents match ASIC3 homomeric properties; currents are absent in ASIC2/3 double knockouts, establishing that ASIC2a and ASIC3 heteromultimerize to form the predominant channels in cardiac DRG neurons. Retrograde labeling, patch-clamp electrophysiology in ASIC-null mice (ASIC2-/-, ASIC3-/-, double KO) Circulation research High 19590043
2012 Triple knockout of ASIC1a, ASIC2, and ASIC3 increases cutaneous mechanosensitivity (enhanced A-mechanonociceptor responses), the opposite of what would be expected if ASICs directly transduce mechanical stimuli, suggesting ASICs modulate rather than directly mediate cutaneous mechanotransduction. Behavioral von Frey assays, single-fiber nerve recordings in triple ASIC knockout mice PloS one Medium 22506072
2012 ASIC1a, ASIC2a, and ASIC3 heteromultimerize to form the principal acid-sensing channels in skeletal muscle afferents. Deletion of ASIC2 selectively abolishes zinc potentiation of acid-evoked currents in muscle afferents, and currents are absent in triple-null mice, establishing the subunit composition of native muscle afferent ASICs. Patch-clamp electrophysiology in labeled muscle afferents from ASIC-null mice, pharmacological profiling (zinc potentiation) FASEB journal High 23109675
2012 Hyperactivation of MDEG/ASIC2 (G430F mutant) causes intracellular Ca2+ overload and ROS production leading to inhibition of proteasomal and autophagic degradation, accumulation of protein aggregates containing caspase-8, and subsequent caspase-8-dependent apoptosis. This pathway is independent of Bax/Bak but dependent on p62 and LC3. Tetracycline-inducible expression system, calcium imaging, ROS measurement, flow cytometry apoptosis assay, caspase activity assay, siRNA knockdown of p62 and LC3 The Journal of biological chemistry High 23239879
2013 ASIC2 is expressed in brain regions of high synaptic density and co-localizes with ASIC1. Loss of ASIC2 decreases freezing behavior in contextual and auditory fear conditioning, predator odor, and CO2 inhalation assays, and increases activity in forced swim, demonstrating that ASIC2 modulates defensive responses to aversive stimuli in vivo. Immunohistochemistry, behavioral assays (fear conditioning, predator odor, CO2, forced swim) in ASIC2-/- mice Genes, brain, and behavior Medium 24256442
2014 ASIC2 subunits increase cell surface expression of ASIC1a-containing channels when co-expressed, and genetic deletion of ASIC2 reduces acid-evoked current amplitude in hippocampal neurons. ASIC2a interacts with PSD-95, and PSD-95 reduces ASIC2a surface expression and current amplitude; this effect requires ASIC2 (absent in ASIC2-/- neurons). Surface biotinylation, patch-clamp electrophysiology in ASIC2-/- hippocampal neurons, co-immunoprecipitation, PSD-95 overexpression PloS one High 24699665
2016 ASIC2 deletion reduces acid-activated current in cortical and striatal neurons but not cerebellar granule neurons (region-specific effect). ASIC2a (but not ASIC2b) facilitates ASIC1a surface trafficking in the brain, and ASIC2 is important for ASIC1a expression levels. ASIC2 deletion reduces ischemia-induced neuronal injury in cortex/hippocampus but not cerebellum, and protects mouse brain from ischemic damage in vivo. Whole-cell patch clamp in neurons from ASIC2-/- mice, surface biotinylation, organotypic slice injury assays, in vivo MCAO stroke model Journal of cerebral blood flow and metabolism High 26861816
2016 Two di-leucine (LL) motifs in the C-terminal juxtamembrane region of ASIC2a act as negative regulators of trafficking: mutating either LL motif increases total and surface ASIC2a expression, enhances dendritic and dendritic spine targeting in hippocampal neurons, increases acid-activated current density, and mutating the second LL motif also increases pH sensitivity. Site-directed mutagenesis, surface biotinylation, electrophysiology, immunofluorescence imaging in organotypic hippocampal slices Molecular brain High 26819004
2016 ASIC2a facilitates surface trafficking of ASIC3 via heteromeric assembly; ASIC3 mostly accumulates in the ER alone but is delivered to the plasma membrane when co-expressed with ASIC2a, confirmed by BiFC assay. ASIC2a-dependent ASIC3 surface expression enhances the sustained component of acid-evoked currents. Surface biotinylation, bimolecular fluorescence complementation (BiFC), electrophysiology in heterologous cells BMB reports Medium 27241858
2016 ASIC2a promotes surface trafficking of ASIC2b via heteromeric assembly. The first transmembrane domain and proximal post-TM1 region (17 amino acids) of ASIC2a are critical for membrane targeting. Replacing corresponding ASIC2b residues with those of ASIC2a confers both proton sensitivity and surface expression to ASIC2b. Chimeric channel construction, surface biotinylation, electrophysiology in heterologous cells Scientific reports Medium 27477936
2017 ASIC2 activates the calcineurin/NFAT1 signaling pathway under acidosis in colorectal cancer cells, promoting invasion and metastasis. Inhibition of calcineurin/NFAT with cyclosporin A blocks ASIC2-induced invasion. ChIP-seq of NFAT1 identified downstream target genes in Rho GTPase and calcium signaling pathways. Gene overexpression/knockdown, matrigel invasion assay, in vivo xenograft/metastasis models, calcineurin inhibitor pharmacology, ChIP-seq Journal of experimental & clinical cancer research Medium 28927426
2018 Psalmotoxin 1 (PcTx1) has dual actions at ASIC1a/ASIC2a heteromeric channels: potent inhibition at desensitizing conditioning pH (IC50=2.9 nM at pH 7.0), and potent potentiation at physiological pH (EC50=56.1 nM in CHO cells; threshold <10 nM in cortical neurons) by increasing channel apparent proton affinity for activation. Whole-cell patch clamp in CHO cells and cortical neurons, concentration-response analysis Scientific reports Medium 29739981
2019 Three N-terminal residues of ASIC2a (T25, T39, and I40) determine rapid resensitization: mutating these residues causes prolonged desensitization (phenocopying ASIC2b) in homomeric and heteromeric channels. This desensitization is not due to channel internalization or degradation. Site-directed mutagenesis, domain-swapping chimeras, whole-cell patch clamp, internalization assays The Journal of general physiology High 31010811
2019 Nocistatin, an endogenous neuropeptide, is a direct agonist of ASIC2a (as well as ASIC1a, ASIC1b, ASIC3), evoking proton-like currents in Xenopus oocytes; the mambalgin-2 antagonist (ASIC1a blocker) inhibits nocistatin-induced currents, suggesting a similar activation mechanism to protons. Xenopus oocyte electrophysiology, pharmacological characterization with peptide toxins Biomolecules Medium 31443477
2020 Ion selectivity in ASIC2a-containing channels is determined differently from ASIC1a: E18' residues at the lower pore are conserved and create energetic preference for Na+ in ASIC2a, but the L7' residues (critical in ASIC1a) do not determine ion permeation in ASIC2a. Instead, ASIC2a-specific negatively charged residues E59 and E62 in the upper pore compensate, making the GAS belt more important for selectivity. Site-directed mutagenesis, whole-cell electrophysiology, molecular dynamics free energy simulations The Journal of general physiology High 31952079
2021 A truncated variant of ASIC2b, whose expression in kidney tubules is induced by luminal albumin and ERK activation, produces sustained acid-stimulated sodium currents when co-expressed with ASIC2a. ASIC2b-null rats in a corticosteroid-clamped nephrotic model do not develop sodium retention, establishing this ASIC2b variant as the mediator of renal Na+ retention in nephrotic syndrome. Xenopus oocyte electrophysiology, ASIC2b-null rat model, renal function measurements, ERK signaling analysis JCI insight High 34166227
2021 ASIC2 and TRPV1 co-localize in aortic baroreceptor nerve endings and form a physical complex confirmed by co-immunoprecipitation and biotin pull-down. In HEK293T cells co-expressing both proteins, inhibition of ASIC2 (but not TRPV1) completely blocks stretch-activated currents, indicating ASIC2 is required upstream of TRPV1 in baroreceptor mechanotransduction. Co-immunoprecipitation, biotin pull-down, cell-attached patch clamp in HEK293T cells, aortic arch nerve recording, immunofluorescence Neuroscience bulletin Medium 34215968
2022 βENaC and ASIC2 form biochemical complexes in vascular smooth muscle cells (co-immunoprecipitation). In renal afferent arterioles, pressure-induced constriction is abolished in ASIC2-/-/βENaCm/m double-mutant mice but only partially impaired in single mutants, demonstrating that βENaC and ASIC2 interact functionally and are jointly required for the full myogenic response. Co-immunoprecipitation from VSMCs, isolated afferent arteriole-attached glomerulus pressure myography in single and double KO mice American journal of physiology. Renal physiology High 35285274
2023 ASIC2 is expressed in proprioceptive sensory neurons. Asic2 loss-of-function mice display impaired muscle spindle responses to stretch and deficits in motor coordination tasks. Analysis of skeletons revealed specific effects on spinal alignment, identifying ASIC2 as a component of proprioceptive sensing. In vivo proprioception behavioral tests, ex vivo muscle spindle electrophysiology, skeletal analysis in Asic2 KO mice Experimental physiology Medium 36951012
2023 ASIC2A (but not ASIC2B) is the predominant ASIC2 subunit in nucleus accumbens core. Recombinant ASIC2A expressed via AAV integrates with endogenous ASIC1A to form functional channels in medium spiny neurons. Loss of ASIC2 alters dendritic spine morphology and increases conditioned place preference to cocaine and morphine, but region-restricted ASIC2A restoration in nucleus accumbens core is insufficient to rescue cocaine/morphine preference. Western blot, AAV-mediated in vivo rescue, patch-clamp electrophysiology in MSNs, conditioned place preference, dendritic spine morphology analysis Frontiers in molecular biosciences Medium 36793786

Source papers

Stage 0 corpus · 59 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 BNaC1 and BNaC2 constitute a new family of human neuronal sodium channels related to degenerins and epithelial sodium channels. Proceedings of the National Academy of Sciences of the United States of America 283 9037075
1996 The mammalian degenerin MDEG, an amiloride-sensitive cation channel activated by mutations causing neurodegeneration in Caenorhabditis elegans. The Journal of biological chemistry 276 8631835
2004 Acid-sensing ion channels ASIC2 and ASIC3 do not contribute to mechanically activated currents in mammalian sensory neurones. The Journal of physiology 205 14990679
2000 Mammalian ASIC2a and ASIC3 subunits co-assemble into heteromeric proton-gated channels sensitive to Gd3+. The Journal of biological chemistry 140 10842183
2001 The PDZ domain protein PICK1 and the sodium channel BNaC1 interact and localize at mechanosensory terminals of dorsal root ganglion neurons and dendrites of central neurons. The Journal of biological chemistry 109 11739374
2003 Amiloride-insensitive currents of the acid-sensing ion channel-2a (ASIC2a)/ASIC2b heteromeric sour-taste receptor channel. The Journal of neuroscience : the official journal of the Society for Neuroscience 104 12736332
2002 Protein kinase C stimulates the acid-sensing ion channel ASIC2a via the PDZ domain-containing protein PICK1. The Journal of biological chemistry 96 12399460
2004 Knockout of the ASIC2 channel in mice does not impair cutaneous mechanosensation, visceral mechanonociception and hearing. The Journal of physiology 94 15169849
2006 Surface expression of ASIC2 inhibits the amiloride-sensitive current and migration of glioma cells. The Journal of biological chemistry 85 16704974
2013 Localization and behaviors in null mice suggest that ASIC1 and ASIC2 modulate responses to aversive stimuli. Genes, brain, and behavior 77 24256442
2009 ASIC2a and ASIC3 heteromultimerize to form pH-sensitive channels in mouse cardiac dorsal root ganglia neurons. Circulation research 77 19590043
2017 The acid-sensing ion channel, ASIC2, promotes invasion and metastasis of colorectal cancer under acidosis by activating the calcineurin/NFAT1 axis. Journal of experimental & clinical cancer research : CR 68 28927426
2012 Simultaneous disruption of mouse ASIC1a, ASIC2 and ASIC3 genes enhances cutaneous mechanosensitivity. PloS one 64 22506072
2012 Acid-sensing ion channels (ASICs) in mouse skeletal muscle afferents are heteromers composed of ASIC1a, ASIC2, and ASIC3 subunits. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 52 23109675
2007 A kinase-anchoring protein 150 and calcineurin are involved in regulation of acid-sensing ion channels ASIC1a and ASIC2a. The Journal of biological chemistry 52 17548344
2008 Impaired pressure-induced constriction in mouse middle cerebral arteries of ASIC2 knockout mice. American journal of physiology. Heart and circulatory physiology 51 18296560
2007 Participation of the chaperone Hsc70 in the trafficking and functional expression of ASIC2 in glioma cells. The Journal of biological chemistry 51 17878160
2012 Ginsenoside-Rd attenuates TRPM7 and ASIC1a but promotes ASIC2a expression in rats after focal cerebral ischemia. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 43 22231470
2007 Proton binding sites involved in the activation of acid-sensing ion channel ASIC2a. Neuroscience letters 40 17881127
2005 The sensory mechanotransduction ion channel ASIC2 (acid sensitive ion channel 2) is regulated by neurotrophin availability. Neuroscience 40 15708491
2008 Hsc70 regulates cell surface ASIC2 expression and vascular smooth muscle cell migration. American journal of physiology. Heart and circulatory physiology 36 18310515
2016 Region specific contribution of ASIC2 to acidosis-and ischemia-induced neuronal injury. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 33 26861816
2014 Altered myogenic vasoconstriction and regulation of whole kidney blood flow in the ASIC2 knockout mouse. American journal of physiology. Renal physiology 31 25520010
2009 The expression of ENa(+)C and ASIC2 proteins in Pacinian corpuscles is differently regulated by TrkB and its ligands BDNF and NT-4. Neuroscience letters 27 19646506
2012 Hyperactivation of the mammalian degenerin MDEG promotes caspase-8 activation and apoptosis. The Journal of biological chemistry 25 23239879
2014 ASIC2 is present in human mechanosensory neurons of the dorsal root ganglia and in mechanoreceptors of the glabrous skin. Histochemistry and cell biology 24 25224144
2019 Inhibitory ASIC2-mediated calcineurin/NFAT against colorectal cancer by triterpenoids extracted from Rhus chinensis Mill. Journal of ethnopharmacology 22 30772482
2018 Dual actions of Psalmotoxin at ASIC1a and ASIC2a heteromeric channels (ASIC1a/2a). Scientific reports 20 29739981
2014 ASIC2 subunits facilitate expression at the cell surface and confer regulation by PSD-95. PloS one 19 24699665
2023 The mechanosensitive ion channel ASIC2 mediates both proprioceptive sensing and spinal alignment. Experimental physiology 17 36951012
2018 High Genetic Risk Scores of ASIC2, MACROD2, CHRM3, and C2orf83 Genetic Variants Associated with Polycystic Ovary Syndrome Impair Insulin Sensitivity and Interact with Energy Intake in Korean Women. Gynecologic and obstetric investigation 17 30343302
2014 Acid-sensing ion channel 2 (ASIC2) is selectively localized in the cilia of the non-sensory olfactory epithelium of adult zebrafish. Histochemistry and cell biology 16 25161120
2012 Immunohistochemical localization of acid-sensing ion channel 2 (ASIC2) in cutaneous Meissner and Pacinian corpuscles of Macaca fascicularis. Neuroscience letters 16 22708125
2016 The Novel ASIC2 Locus is Associated with Severe Gingival Inflammation. JDR clinical and translational research 15 28459102
2011 Acid-sensing ion channel 2 (ASIC2) in the intestine of adult zebrafish. Neuroscience letters 15 21356277
2003 Molecular cloning and characterization of human acid sensing ion channel (ASIC)2 gene promoter. Gene 15 12957380
2019 Endogenous Neuropeptide Nocistatin Is a Direct Agonist of Acid-Sensing Ion Channels (ASIC1, ASIC2 and ASIC3). Biomolecules 14 31443477
2021 Pterostilbene alleviates pulmonary fibrosis by regulating ASIC2. Chinese medicine 13 34321072
2016 Two di-leucine motifs regulate trafficking and function of mouse ASIC2a. Molecular brain 13 26819004
2020 Determinants of ion selectivity in ASIC1a- and ASIC2a-containing acid-sensing ion channels. The Journal of general physiology 12 31952079
2011 Knockdown of ASIC2a subunit aggravates injury of rat C6 glioma cells in acidosis. Journal of physiology and biochemistry 11 21061195
2017 ASIC2a overexpression enhances the protective effect of PcTx1 and APETx2 against acidosis-induced articular chondrocyte apoptosis and cytotoxicity. Gene 10 29141196
2008 Expression of ASIC2 in ciliated cells and stereociliated cells. Cell and tissue research 10 18560896
2021 A variant of ASIC2 mediates sodium retention in nephrotic syndrome. JCI insight 9 34166227
2018 Walnut oil improves spatial memory in rats and increases the expression of acid-sensing ion channel genes Asic2a and Asic4. Food science & nutrition 9 30680184
2016 Acid-Sensing Ion Channel 2a (ASIC2a) Promotes Surface Trafficking of ASIC2b via Heteromeric Assembly. Scientific reports 9 27477936
2023 Investigating role of ASIC2 in synaptic and behavioral responses to drugs of abuse. Frontiers in molecular biosciences 8 36793786
2019 High Expression of Acid-Sensing Ion Channel 2 (ASIC2) in Bone Cells in Osteoporotic Vertebral Fractures. BioMed research international 8 31531354
2012 Immunohistochemical detection of the putative mechanoproteins ASIC2 and TRPV4 in avian herbst sensory corpuscles. Anatomical record (Hoboken, N.J. : 2007) 8 23152301
2022 βENaC and ASIC2 associate in VSMCs to mediate pressure-induced constriction in the renal afferent arteriole. American journal of physiology. Renal physiology 6 35285274
2024 Potential Implications of Acid-Sensing Ion Channels ASIC2 and ASIC4 in Gonadal Differentiation of Dicentrarchus labrax Subjected to Water Temperature Increase during Gonadal Development. Animals : an open access journal from MDPI 5 38612263
2016 ASIC2a-dependent increase of ASIC3 surface expression enhances the sustained component of the currents. BMB reports 5 27241858
2007 Characterization of human ASIC2a homomeric channels stably expressed in murine Ltk- cells. Life sciences 5 18054963
2021 ASIC2 Synergizes with TRPV1 in the Mechano-Electrical Transduction of Arterial Baroreceptors. Neuroscience bulletin 4 34215968
2010 The acid-sensing ion channel 2 (ASIC2) of ciliated cells in the developing rat nasal septum. Archives of histology and cytology 3 21566334
2025 Ion-Channel Proteins in the Prepubertal Bitch Reproductive System: The Immunolocalization of ASIC2, ASIC4, and PIEZO2. International journal of molecular sciences 2 40362625
2025 The relationship between acid-sensing ion channel, ASIC2, and oncogenic β-catenin signaling in ovarian cancer. Scientific reports 2 40437028
2024 Bone marrow monocytes and macrophages from mice lacking βENaC and ASIC2 have a reduced chemotactic migration response and polarization. Physiological reports 1 39016176
2019 Rapid resensitization of ASIC2a is conferred by three amino acid residues in the N terminus. The Journal of general physiology 1 31010811

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