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ASIC3

gene
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Also known as TNaC1DRASIC

Summary

ASIC3 (acid sensing ion channel subunit 3, HGNC:101) is a protein-coding gene on chromosome 7q36.1, encoding Acid-sensing ion channel 3 (Q9UHC3). Forms pH-gated heterotrimeric sodium channels that act as postsynaptic excitatory receptors in the nervous system.

This gene encodes a member of the degenerin/epithelial sodium channel (DEG/ENaC) superfamily. The members of this family are amiloride-sensitive sodium channels that contain intracellular N and C termini, two hydrophobic transmembrane regions, and a large extracellular loop, which has many cysteine residues with conserved spacing. The member encoded by this gene is an acid sensor and may play an important role in the detection of lasting pH changes. In addition, a heteromeric association between this member and acid-sensing (proton-gated) ion channel 2 has been observed as proton-gated channels sensitive to gadolinium. Alternatively spliced transcript variants have been described.

Source: NCBI Gene 9311 — RefSeq curated summary.

At a glance

  • GWAS associations: 1
  • Clinical variants (ClinVar): 133 total — 1 pathogenic
  • Druggable target: yes — 1 molecules with ChEMBL bioactivity
  • MANE Select transcript: NM_004769

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:101
Approved symbolASIC3
Nameacid sensing ion channel subunit 3
Location7q36.1
Locus typegene with protein product
StatusApproved
AliasesTNaC1, DRASIC
Ensembl geneENSG00000213199
Ensembl biotypeprotein_coding
OMIM611741
Entrez9311

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 6 protein_coding, 2 nonsense_mediated_decay, 2 retained_intron

ENST00000297512, ENST00000349064, ENST00000357922, ENST00000377904, ENST00000468325, ENST00000474135, ENST00000485929, ENST00000490540, ENST00000498105, ENST00000962796

RefSeq mRNA: 3 — MANE Select: NM_004769 NM_004769, NM_020321, NM_020322

CCDS: CCDS5914, CCDS5915, CCDS5916

Canonical transcript exons

ENST00000349064 — 11 exons

ExonStartEnd
ENSE00001088222151051172151051319
ENSE00001088224151050758151050953
ENSE00001088239151050106151050256
ENSE00001900066151048531151049419
ENSE00002503559151050481151050608
ENSE00003488528151051039151051095
ENSE00003532275151052416151052474
ENSE00003563324151052574151052754
ENSE00003596447151051983151052062
ENSE00003659648151051810151051901
ENSE00003689739151052166151052237

Expression profiles

Bgee: expression breadth ubiquitous, 179 present calls, max score 97.27.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2776 / max 21.9539, expressed in 79 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter IDTPM avgSamples expressed
820380.268977
820370.00873

Top tissues by expression

287 total, by Bgee expression score (0-100, higher = more expressed):

TissueAnatomy IDExpression scoreQuality
right hemisphere of cerebellumUBERON:001489097.27gold quality
cerebellar hemisphereUBERON:000224596.62gold quality
cerebellar cortexUBERON:000212996.40gold quality
right testisUBERON:000453493.28gold quality
cerebellumUBERON:000203793.18gold quality
left testisUBERON:000453392.90gold quality
right frontal lobeUBERON:000281092.05gold quality
apex of heartUBERON:000209891.69gold quality
C1 segment of cervical spinal cordUBERON:000646991.56gold quality
adenohypophysisUBERON:000219691.42gold quality
nucleus accumbensUBERON:000188289.80gold quality
pituitary glandUBERON:000000789.29gold quality
caudate nucleusUBERON:000187388.83gold quality
putamenUBERON:000187488.17gold quality
anterior cingulate cortexUBERON:000983587.96gold quality
cingulate cortexUBERON:000302787.95gold quality
testisUBERON:000047387.90gold quality
spinal cordUBERON:000224087.57gold quality
right uterine tubeUBERON:000130286.00gold quality
amygdalaUBERON:000187685.91gold quality
Brodmann (1909) area 9UBERON:001354085.74gold quality
hypothalamusUBERON:000189885.31gold quality
primordial germ cell in gonadCL:0000670 ∩ UBERON:000099184.38gold quality
body of uterusUBERON:000985383.91gold quality
endocervixUBERON:000045883.83gold quality
male germ line stem cell (sensu Vertebrata) in testisCL:0000089 ∩ UBERON:000047382.97gold quality
dorsolateral prefrontal cortexUBERON:000983482.82gold quality
muscle layer of sigmoid colonUBERON:003580582.61gold quality
heart left ventricleUBERON:000208482.47gold quality
prefrontal cortexUBERON:000045182.15gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

ExperimentMarker?Max mean expression
E-ANND-3no1.81

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, SMAD3

miRNA regulators (miRDB)

8 targeting ASIC3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNAMax scoreAvg scoremiRNA target_count
HSA-MIR-426098.7865.37848
HSA-MIR-557298.5565.84970
HSA-MIR-6819-5P97.9666.591071
HSA-MIR-450A-2-3P97.9167.561459
HSA-MIR-6737-5P97.7566.541044
HSA-MIR-6812-5P97.5665.391059
HSA-MIR-3117-3P95.9667.82473
HSA-MIR-808395.9367.55694

Literature-anchored findings (GeneRIF, showing 32)

  • role in modulating high-intensity pain stimuli (PMID:12060708)
  • PSD-95 and Lin-7b interact with acid-sensing ion channel-3 and have opposite effects on H+- gated current (PMID:15317815)
  • Diclofenac studies show ASIC3 is a significant contributor to cutaneous acid-induced pain. (PMID:15574747)
  • the interaction of ASIC3 and CFTR may contribute to defective salt and fluid transepithelial transport in the cystic fibrotic pulmonary system (PMID:17012229)
  • These results suggest that the ASIC3 may be involved in blood pressure regulation. (PMID:18854755)
  • The biological features of ASIC3 is discussed and recent advances on the role of ASIC3 in the pathogenesis and treatment of arthritis pain, are summarized. (PMID:19885742)
  • an independent association between an ASIC3 genetic polymorphism and insulin resistance in Taiwanese (PMID:20416288)
  • Neither ASIC3 or ASIC1 knockout influences the development or maintenance of experimental neuropathic pain after nerve injury. (PMID:20693874)
  • Used coincidentally by sensory neurons to detect lactic acidosis, ASIC3 (amiloride-sensitive cation channel 3) interacts with adenosine triphosphate (ATP) to detect muscle ischemia. (PMID:21092862)
  • Atomic level characterization of the nonproton ligand-sensing domain of ASIC3 channels. (PMID:21586569)
  • The results showed that there was a significant increase in the mean relative optical density of ASIC2 and ASIC3 but not ASIC1a in the lining epithelium and glandular tubes of gastric mucosa in patients with Henoch-Schonlein purpura. (PMID:22157923)
  • A mechanism of induction of ASIC-3 expression relevant to AR was suggested by the finding that eosinophil peroxidase (EPO), acting via ERK1/2, induced the expression of ASIC-3 in epithelial cells. (PMID:22702502)
  • The highly proton sensitive ASIC3 channels are predominantly distributed in peripheral sensory neurons, correlating with their roles in multimodal sensory perception, including nociception, mechanosensation, and chemosensation. (PMID:22778854)
  • CAR and ASIC3 co-immunoprecipitate only when co-expressed with PSD-95. (PMID:22809504)
  • ASIC3 is able to sense the extracellular pH in both directions and to dynamically adapt its activity between pH 5.0 and 8.0, playing a role in fine tuning neuronal membrane potentials and neuron sensitization in various pH environments. (PMID:22829666)
  • Experiments with Asic3 inhibitors show that Asic3 inhibition leads to loss of pressure-induced vasodilation due to pressure detection failure rather than endothelial mechanisms. (PMID:22842475)
  • Lignan from thyme possesses inhibitory effect on ASIC3 channel current. (PMID:22854960)
  • Sea anemone peptide with uncommon beta-hairpin structure inhibits acid-sensing ion channel 3 (ASIC3) and reveals analgesic activity. (PMID:23801332)
  • Blocking ASIC3 in interneurons from temporal lobe epilepsy patients decreased the frequency of action potential firing. (PMID:25476599)
  • This study suggests that ASIC23may play a role as mediators of inflammatory pain and be involved in the pathogenesis of frozen shoulder. (PMID:26033064)
  • These findings open new perspectives on the roles of ASIC3 in the absence of tissue pH variation, as well as on the contribution of those channels to lipid-mediated signaling. (PMID:26772186)
  • Acidic pH resulted in an increase in ASIC-3 expressionin the discs of paitents with intervertebral disc degeneration. (PMID:27853274)
  • Respiratory syncytial virus and measles virus infection upregulates ASICS3 expression in bronchial epithelial cells. (PMID:28187208)
  • the data demonstrate a functional link between ASICs and [Ca(2+)]i/RhoA pathway, which contributes to the acidity-induced epithelial-mesenchymal transition. (PMID:28518134)
  • The results show that acid-sensing ion channel 1, acid-sensing ion channel 2, and acid-sensing ion channel 3 are expressed in A549 cells at the messenger RNA and protein levels, and acid-sensing ion channel-like currents were elicited by extracellular acid stimuli. (PMID:28618956)
  • The present review discusses the dual nature of ASIC3 in joint inflammation with possible mechanisms. (PMID:30035658)
  • Heartburn sensation in nonerosive reflux disease: pattern of superficial sensory nerves expressing TRPV1 and epithelial cells expressing ASIC3 receptors. (PMID:33655767)
  • ASIC1 and ASIC3 mediate cellular senescence of human nucleus pulposus mesenchymal stem cells during intervertebral disc degeneration. (PMID:33824228)
  • TRPV1 Responses in the Cerebellum Lobules VI, VII, VIII Using Electroacupuncture Treatment for Chronic Pain and Depression Comorbidity in a Murine Model. (PMID:34068557)
  • Upregulation of acid sensing ion channels is associated with esophageal hypersensitivity in GERD. (PMID:34918385)
  • Lysophosphatidylcholine 16:0 mediates chronic joint pain associated to rheumatic diseases through acid-sensing ion channel 3. (PMID:35086123)
  • Acid-sensing ion channel 3 is a new potential therapeutic target for the control of glioblastoma cancer stem cells growth. (PMID:39227705)

Cross-species orthologs

26 orthologs

OrganismSymbolGene ID
mus_musculusAsic3ENSMUSG00000038276
rattus_norvegicusAsic3ENSRNOG00000008380
drosophila_melanogasterNachFBGN0024319
drosophila_melanogasterppk28FBGN0030795
drosophila_melanogasterppk17FBGN0032602
drosophila_melanogasterppk6FBGN0034489
drosophila_melanogasterppk12FBGN0034730
drosophila_melanogasterppk29FBGN0034965
drosophila_melanogasterppk24FBGN0039839
drosophila_melanogasterppk22FBGN0051105
drosophila_melanogasterppk8FBGN0052792
drosophila_melanogasterppk5FBGN0053289
drosophila_melanogasterppk16FBGN0065108
drosophila_melanogasterppk11FBGN0065109
drosophila_melanogasterppk9FBGN0085398
drosophila_melanogasterppk18FBGN0265001
caenorhabditis_elegansWBGENE00003168
caenorhabditis_elegansWBGENE00003174
caenorhabditis_elegansWBGENE00007518
caenorhabditis_elegansWBGENE00009073
caenorhabditis_elegansWBGENE00011891
caenorhabditis_elegansdelm-2WBGENE00016063
caenorhabditis_elegansacd-1WBGENE00016064
caenorhabditis_elegansacd-2WBGENE00016066
caenorhabditis_elegansWBGENE00016699
caenorhabditis_elegansWBGENE00017879

Paralogs (8): ASIC4 (ENSG00000072182), ASIC2 (ENSG00000108684), ASIC1 (ENSG00000110881), SCNN1A (ENSG00000111319), SCNN1D (ENSG00000162572), SCNN1G (ENSG00000166828), SCNN1B (ENSG00000168447), ASIC5 (ENSG00000256394)

Protein

Protein identifiers

Acid-sensing ion channel 3 — Q9UHC3 (reviewed: Q9UHC3)

Alternative names: Amiloride-sensitive cation channel 3, Neuronal amiloride-sensitive cation channel 3, Testis sodium channel 1

All UniProt accessions (6): A0A090N7X8, A0A090N8Q1, A0A090N8Z6, Q9UHC3, H7C4W0, H7C5N6

UniProt curated annotations — full annotation on UniProt →

Function. Forms pH-gated heterotrimeric sodium channels that act as postsynaptic excitatory receptors in the nervous system. Upon extracellular acidification, these channels generate a biphasic current with a fast inactivating and a slow sustained phase. ASIC3 is more sensitive to protons and gates between closed, open, and desensitized states faster than other ASICs. Displays high selectivity for sodium ions but can also permit the permeation of other cations. As a neuronal acid sensor, probably contributes to mechanoreception, acid nociception, and heat nociception. 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.

Subunit / interactions. Can form homotrimeric channels. Heterotrimer; forms functional heterotrimers producing channel with different properties. Forms heterotrimers with ASIC2; gives rise to a biphasic current with a sustained current which discriminates poorly between Na(+) and K(+). Interacts with STOM; inhibits ASIC3 acid-evoked current. Interacts with LIN7B (via PDZ domain); increases ASIC3 expression at the plasma membrane. Interacts with MAGI1 (via PDZ domain); probably regulates ASIC3. Interacts with GOPC (via PDZ domain); probably regulates ASIC3. Interacts with DLG4 (via PDZ domain); reduces ASIC3 expression at the plasma membrane.

Subcellular location. Cell membrane. Cytoplasm.

Tissue specificity. Expressed by sensory neurons. Strongly expressed in brain, spinal cord, lung, lymph nodes, kidney, pituitary, heart and testis.

Activity regulation. Inhibited by the diuretic drug amiloride. Inhibited by the diuretic drug triamterene. Potentiated by the vertebrate neuropeptide FF (NPFF) and the related FMRFamide. Specifically and reversibly inhibited by the a sea anemone toxin APETx2.

Domain organisation. The PDZ-binding motif mediates the interaction with PDZ-domain containing proteins including DLG4, GOPC, MAGI1 and LIN7A.

Similarity. Belongs to the amiloride-sensitive sodium channel (TC 1.A.6) family. ASIC3 subfamily.

Isoforms (4)

UniProt IDNamesCanonical?
Q9UHC3-11yes
Q9UHC3-22, ASIC3b
Q9UHC3-33, ASIC3c
Q9UHC3-44, c

RefSeq proteins (3): NP_004760, NP_064717, NP_064718 (=MANE)

Domains & families (InterPro)

IDNameType
IPR001873ENaCFamily
IPR004724ENaC_chordatesFamily
IPR020903ENaC_CSConserved_site

Pfam: PF00858

Catalyzed reactions (Rhea), 3 shown:

  • K(+)(in) = K(+)(out) (RHEA:29463)
  • Ca(2+)(in) = Ca(2+)(out) (RHEA:29671)
  • Na(+)(in) = Na(+)(out) (RHEA:34963)

UniProt features (35 total): sequence conflict 8, disulfide bond 7, splice variant 4, mutagenesis site 4, topological domain 3, glycosylation site 2, transmembrane region 2, short sequence motif 2, chain 1, sequence variant 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-Q9UHC3-F183.150.60

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (7): 92–186, 164–171, 282–370, 315–366, 319–364, 328–350, 330–342

Glycosylation sites (2): 398, 175

Mutagenesis-validated functional residues (4):

PositionPhenotype
528no effect on interaction with lin7b. no effect on interaction with magi1. no effect on interaction with gopc.
529loss of interaction with lin7b. loss of interaction with magi1.
530loss of interaction with gopc. no effect on interaction with lin7b. no effect on interaction with magi1.
531loss of interaction with lin7b. loss of interaction with magi1. loss of interaction with gopc.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

IDPathway
R-HSA-2672351Stimuli-sensing channels
R-HSA-382551Transport of small molecules
R-HSA-983712Ion channel transport

MSigDB gene sets: 106 (showing top): GOBP_MEMBRANE_DEPOLARIZATION, GOBP_SENSORY_PERCEPTION_OF_TEMPERATURE_STIMULUS, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_DETECTION_OF_MECHANICAL_STIMULUS_INVOLVED_IN_SENSORY_PERCEPTION, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, SP3_Q3, GOBP_SENSORY_PERCEPTION_OF_CHEMICAL_STIMULUS, GOBP_MONOATOMIC_CATION_TRANSPORT, SHEDDEN_LUNG_CANCER_GOOD_SURVIVAL_A5, GOBP_DETECTION_OF_MECHANICAL_STIMULUS, GOBP_SENSORY_PERCEPTION_OF_PAIN, GOBP_DETECTION_OF_TEMPERATURE_STIMULUS, MODULE_379, GOBP_SENSORY_PERCEPTION_OF_TASTE, GOBP_RESPONSE_TO_ABIOTIC_STIMULUS

GO Biological Process (18): response to heat (GO:0009408), response to acidic pH (GO:0010447), sodium ion transmembrane transport (GO:0035725), sensory perception of sour taste (GO:0050915), detection of temperature stimulus involved in sensory perception of pain (GO:0050965), detection of mechanical stimulus involved in sensory perception of pain (GO:0050966), detection of chemical stimulus involved in sensory perception of pain (GO:0050968), establishment of localization in cell (GO:0051649), membrane depolarization (GO:0051899), monoatomic ion transport (GO:0006811), monoatomic cation transport (GO:0006812), sodium ion transport (GO:0006814), response to mechanical stimulus (GO:0009612), monoatomic ion transmembrane transport (GO:0034220), enterobactin transport (GO:0042930), detection of chemical stimulus involved in sensory perception (GO:0050907), detection of temperature stimulus involved in sensory perception (GO:0050961), detection of mechanical stimulus involved in sensory perception (GO:0050974)

GO Molecular Function (6): sodium channel activity (GO:0005272), ligand-gated sodium channel activity (GO:0015280), monoatomic ion-gated channel activity (GO:0022839), pH-gated sodium channel activity (GO:0160125), pH-gated monoatomic ion channel activity (GO:0160128), monoatomic cation channel activity (GO:0005261)

GO Cellular Component (3): cytoplasm (GO:0005737), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

CategoryPathways
Ion channel transport1
Transport of small molecules1

GO top-level categories

Rollup of top GO terms by namespace:

CategoryTerms
sensory perception of pain3
sensory perception3
detection of stimulus involved in sensory perception3
monoatomic ion transport2
cellular anatomical structure2
response to stress1
response to temperature stimulus1
response to pH1
sodium ion transport1
monoatomic cation transmembrane transport1
sensory perception of taste1
detection of temperature stimulus involved in sensory perception1
detection of mechanical stimulus involved in sensory perception1
detection of chemical stimulus involved in sensory perception1
establishment of localization1
cellular localization1
regulation of membrane potential1
transport1
metal ion transport1
response to external stimulus1
response to abiotic stimulus1
transmembrane transport1
organic hydroxy compound transport1
siderophore transport1
sensory perception of chemical stimulus1
detection of chemical stimulus1
detection of temperature stimulus1
sensory perception of temperature stimulus1
sensory perception of mechanical stimulus1
detection of mechanical stimulus1
monoatomic cation channel activity1
sodium ion transmembrane transporter activity1
sodium channel activity1
ligand-gated monoatomic cation channel activity1
ligand-gated channel activity1
ligand-gated sodium channel activity1
pH-gated monoatomic ion channel activity1
ligand-gated monoatomic ion channel activity1
monoatomic ion channel activity1
monoatomic cation transmembrane transporter activity1

Protein interactions and networks

STRING

806 interactions, top by confidence (×1000):

Protein AProtein BPartner UniProtScore
ASIC3TRPV1Q8NER1822
ASIC3P2RX5Q93086723
ASIC3P2RX3P56373700
ASIC3ASIC4Q96FT7699
ASIC3TRPA1O75762680
ASIC3P2RX4Q99571658
ASIC3SCN10AQ9Y5Y9640
ASIC3SCN9AQ15858632
ASIC3PICK1Q9NRD5613
ASIC3PIEZO2Q9H5I5608
ASIC3TRPV4Q9HBA0605
ASIC3STOML3Q8TAV4596
ASIC3MAGI1Q96QZ7592
ASIC3TRPM8Q7Z2W7588
ASIC3STOMP27105584

IntAct

216 interactions, top by confidence:

ABTypeScore
ASIC3DLG4psi-mi:“MI:0407”(direct interaction)0.610
ASIC3SNX27psi-mi:“MI:0407”(direct interaction)0.610
ASIC3SCRIBpsi-mi:“MI:0407”(direct interaction)0.610
ASIC3MAST2psi-mi:“MI:0407”(direct interaction)0.610
DLG4ASIC3psi-mi:“MI:0407”(direct interaction)0.610
ASIC3DLG4psi-mi:“MI:0915”(physical association)0.610
ASIC3SNX27psi-mi:“MI:0915”(physical association)0.610
ASIC3SCRIBpsi-mi:“MI:0915”(physical association)0.610
ASIC3MAST2psi-mi:“MI:0915”(physical association)0.610
ASIC3ARHGEF12psi-mi:“MI:0407”(direct interaction)0.440
ASIC3SHANK3psi-mi:“MI:0407”(direct interaction)0.440
ASIC3PDZD7psi-mi:“MI:0407”(direct interaction)0.440
ASIC3NHERF1psi-mi:“MI:0407”(direct interaction)0.440
ASIC3MAGI1psi-mi:“MI:0407”(direct interaction)0.440
ASIC3TAX1BP3psi-mi:“MI:0407”(direct interaction)0.440
ASIC3SHANK2psi-mi:“MI:0407”(direct interaction)0.440
ASIC3SHANK1psi-mi:“MI:0407”(direct interaction)0.440
ASIC3HTRA4psi-mi:“MI:0407”(direct interaction)0.440
ASIC3ARHGEF11psi-mi:“MI:0407”(direct interaction)0.440
ASIC3PDZK1psi-mi:“MI:0407”(direct interaction)0.440
ASIC3GOPCpsi-mi:“MI:0407”(direct interaction)0.440
ASIC3TAMALINpsi-mi:“MI:0407”(direct interaction)0.440
ASIC3MPDZpsi-mi:“MI:0407”(direct interaction)0.440

BioGRID (14): ASIC3 (Affinity Capture-Western), MAGI1 (Two-hybrid), LIN7B (Affinity Capture-Western), GOPC (Affinity Capture-Western), MAGI1 (Affinity Capture-Western), DLG4 (Affinity Capture-Western), ASIC3 (Biochemical Activity), ASIC3 (Affinity Capture-Western), GOPC (Two-hybrid), LIN7B (Two-hybrid), ASIC3 (Co-fractionation), ASIC3 (Co-fractionation), ASIC3 (Co-fractionation), ASIC3 (Co-fractionation)

ESM2 similar proteins: A5D7U4, F1MJW3, H1AFJ5, H1AFJ6, H1AFJ7, H2LRU7, H2QAR5, H2QAR6, H9GBX2, K7FQW8, K7FSQ4, K7GET2, O13262, O13263, O35240, O62816, O70397, O97742, P24585, P24612, P34886, P37090, P37091, P49653, P51167, P51168, P51169, P51170, P51171, P78348, Q17298, Q19038, Q28738, Q60NC0, Q62765, Q62889, Q6NXK8, Q6X1Y6, Q708S3, Q708S7

Diamond homologs: O35240, P55926, P78348, Q10025, Q16515, Q1XA76, Q62962, Q6NXK8, Q6X1Y6, Q708S3, Q708S4, Q708S5, Q708S6, Q708S7, Q708S8, Q7T1N4, Q7TNS7, Q925H0, Q96FT7, Q9JHS6, Q9NY37, Q9R0W5, Q9R0Y1, Q9UHC3, Q25011, P24585, P24612, P34886, Q09274, Q17298, Q19038, O13262, O97742, P51169, Q21974, Q9WU38, O13263, P37090, Q9W754, O01635

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 115 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

PathwayPartnersFoldFDR
Ras activation upon Ca2+ influx through NMDA receptor541.4×6e-06
Unblocking of NMDA receptors, glutamate binding and activation539.4×6e-06
Negative regulation of NMDA receptor-mediated neuronal transmission539.4×6e-06
Long-term potentiation534.5×1e-05
Tight junction interactions632.0×2e-06
Neurexins and neuroligins1028.5×4e-10
Assembly and cell surface presentation of NMDA receptors725.8×1e-06
Protein-protein interactions at synapses519.2×1e-04

GO biological processes:

GO termPartnersFoldFDR
establishment or maintenance of epithelial cell apical/basal polarity1580.7×2e-23
protein localization to synapse749.6×9e-09
receptor clustering740.5×4e-08
regulation of postsynaptic membrane neurotransmitter receptor levels836.7×9e-09
positive regulation of excitatory postsynaptic potential629.3×4e-06
establishment or maintenance of cell polarity622.3×1e-05
social behavior512.6×1e-03
protein-containing complex assembly1010.5×3e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

133 variants total. Per-class counts are floors (≥ shown; pagination cap):

ClassificationCount (floor)
Pathogenic1
Likely pathogenic0
Uncertain significance107
Likely benign14
Benign2

Top pathogenic / likely-pathogenic (1)

Variant IDHGVSClassification
146075GRCh38/hg38 7p22.3-q36.3(chr7:54185-159282390)x1Pathogenic

SpliceAI

1451 predictions. Top by Δscore:

VariantEffectΔscore
7:151051036:CAGG:Cacceptor_loss1.0000
7:151051037:A:AGacceptor_gain1.0000
7:151051038:G:GAacceptor_gain1.0000
7:151051038:GGC:Gacceptor_gain1.0000
7:151051290:G:GTdonor_gain1.0000
7:151051309:GCC:Gdonor_gain1.0000
7:151051315:ATCGC:Adonor_gain1.0000
7:151051316:TCGC:Tdonor_gain1.0000
7:151051318:GC:Gdonor_gain1.0000
7:151051318:GCGTG:Gdonor_loss1.0000
7:151051319:CGTGA:Cdonor_loss1.0000
7:151051320:G:GGdonor_gain1.0000
7:151051320:GTGAG:Gdonor_loss1.0000
7:151051321:T:Adonor_loss1.0000
7:151051325:C:Gdonor_gain1.0000
7:151051808:A:AGacceptor_gain1.0000
7:151051809:G:GGacceptor_gain1.0000
7:151051873:G:GTdonor_gain1.0000
7:151051885:G:GTdonor_gain1.0000
7:151051885:GAT:Gdonor_gain1.0000
7:151051897:GCTTG:Gdonor_gain1.0000
7:151051899:TTGGT:Tdonor_loss1.0000
7:151051900:TG:Tdonor_loss1.0000
7:151051901:GG:Gdonor_loss1.0000
7:151051902:G:GGdonor_gain1.0000
7:151051904:G:GGdonor_gain1.0000
7:151051978:CACAG:Cacceptor_loss1.0000
7:151051980:CAGGT:Cacceptor_loss1.0000
7:151051981:A:AGacceptor_gain1.0000
7:151051981:A:Tacceptor_loss1.0000

AlphaMissense

3450 scored. Top likely-pathogenic:

VariantProtein changeam_pathogenicity
7:151050127:T:AC186S0.996
7:151050128:G:CC186S0.996
7:151051053:T:AC342S0.996
7:151051054:G:CC342S0.996
7:151049159:T:AC92S0.995
7:151049160:G:CC92S0.995
7:151050129:C:GC186W0.995
7:151050137:T:CF189S0.995
7:151052021:A:CS449R0.995
7:151052023:C:AS449R0.995
7:151052023:C:GS449R0.995
7:151051053:T:CC342R0.994
7:151051054:G:AC342Y0.994
7:151051055:C:GC342W0.994
7:151049142:T:GF86C0.993
7:151049161:C:GC92W0.993
7:151049164:C:AN93K0.993
7:151049164:C:GN93K0.993
7:151049412:T:CF176S0.993
7:151050127:T:CC186R0.993
7:151050926:T:AC328S0.993
7:151050927:G:CC328S0.993
7:151050932:T:AC330S0.993
7:151050933:G:CC330S0.993
7:151049160:G:AC92Y0.992
7:151049412:T:GF176C0.992
7:151050137:T:GF189C0.992
7:151050141:C:AN190K0.991
7:151050141:C:GN190K0.991
7:151049151:T:AV89D0.990

dbSNP variants (sampled 300 via entrez): RS1000432561 (7:151052691 C>G,T), RS1000790542 (7:151048333 C>A), RS1001062521 (7:151053256 C>G,T), RS1001389994 (7:151047280 C>A,T), RS1001435942 (7:151051373 G>C), RS1001737958 (7:151047019 C>A,T), RS1002620719 (7:151050879 T>C), RS1002839997 (7:151049128 C>T), RS1002894418 (7:151049259 T>A,C), RS1003846726 (7:151048400 C>T), RS1003904420 (7:151053063 C>A), RS1004306896 (7:151048555 C>G), RS1004570668 (7:151050941 G>A), RS1004810664 (7:151047578 G>C), RS1004902130 (7:151047449 C>A,G)

Disease associations

OMIM: gene MIM:611741 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

StudyTraitp-value
GCST003476_9Eyebrow thickness7.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5368 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 63,705 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

MoleculeNamePhasePatents
CHEMBL945AMILORIDE463,705

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: lgic — Acid-sensing (proton-gated) ion channels (ASICs)

Most potent curated ligand interactions (17 total), top 17:

LigandActionAffinityParameter
APETx2Channel blocker7.2pIC50
diminazeneChannel blocker6.5pIC50
A-317567Channel blocker5.99pIC50
NS383Channel blocker5.7pIC50
nafamostatChannel blocker5.6pIC50
lysophosphatidylcholinePartial agonist5.4pEC50
Ugr 9-1Channel blocker5.0pIC50
amilorideChannel blocker4.8pIC50
Gd3+Channel blocker4.4pIC50
H+Activator4.3pEC50
Zn2+Channel blocker4.2pIC50
diclofenacChannel blocker4.0pIC50
aspirinChannel blocker4.0pIC50
salicylic acidChannel blocker3.6pIC50
GMQActivator3.0pEC50
arcaineActivator2.9pEC50
agmatineActivator2.0pEC50

ChEMBL bioactivities

30 potent at pChembl≥5 of 50 total, top 30 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChemblTypeValueUnitMolecule
6.72IC50190nMCHEMBL1800440
6.66IC50220nMCHEMBL1800430
6.64IC50230nMCHEMBL1800432
6.64IC50230nMCHEMBL1800436
6.57IC50270nMCHEMBL1800428
6.51IC50310nMCHEMBL1800433
6.34IC50460nMCHEMBL1800331
6.31IC50490nMCHEMBL513153
6.29IC50510nMCHEMBL466668
6.29IC50510nMCHEMBL1800437
6.19IC50640nMCHEMBL467724
6.17IC50680nMCHEMBL1800431
5.92IC501200nMCHEMBL1770740
5.77IC501700nMCHEMBL1770745
5.60IC502500nMCHEMBL1800438
5.58IC502600nMCHEMBL1770739
5.55IC502800nMCHEMBL1800427
5.51IC503100nMCHEMBL1770750
5.48IC503300nMCHEMBL1770744
5.47IC503400nMCHEMBL1800334
5.42IC503800nMCHEMBL1770752
5.37IC504300nMCHEMBL1800439
5.36IC504400nMAMILORIDE
5.32IC504800nMCHEMBL1800333
5.24IC505800nMCHEMBL1770741
5.20IC506300nMCHEMBL1800332
5.16IC506900nMCHEMBL1770738
5.15IC507100nMCHEMBL1770746
5.05IC509000nMCHEMBL1770730
5.02IC509600nMCHEMBL1770753

PubChem BioAssay actives

30 with measured affinity, of 220 total; 30 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

CompoundAssayTypeValueUnit
4-[2-[2-(aminomethyl)-3-chloro-1-benzothiophen-6-yl]ethynyl]-N,N-dimethyl-2,3-dihydro-1H-inden-1-amine607550: Inhibition of ASIC3 assessed as inhibition of peak current by electrophysiology methodic500.1900uM
[3-chloro-6-[2-(1,2,3,4-tetrahydroisoquinolin-7-yl)ethynyl]-1-benzothiophen-2-yl]methanamine607550: Inhibition of ASIC3 assessed as inhibition of peak current by electrophysiology methodic500.2200uM
[3-chloro-6-[2-(2-ethyl-3,4-dihydro-1H-isoquinolin-7-yl)ethynyl]-1-benzothiophen-2-yl]methanamine607550: Inhibition of ASIC3 assessed as inhibition of peak current by electrophysiology methodic500.2300uM
5-[2-[2-(aminomethyl)-3-chloro-1-benzothiophen-6-yl]ethynyl]-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-1-amine607550: Inhibition of ASIC3 assessed as inhibition of peak current by electrophysiology methodic500.2300uM
[3-chloro-6-[2-(1,2-dimethyl-3,4-dihydro-1H-isoquinolin-7-yl)ethynyl]-1-benzothiophen-2-yl]methanamine607550: Inhibition of ASIC3 assessed as inhibition of peak current by electrophysiology methodic500.2700uM
[3-chloro-6-[2-(2-propan-2-yl-3,4-dihydro-1H-isoquinolin-7-yl)ethynyl]-1-benzothiophen-2-yl]methanamine607550: Inhibition of ASIC3 assessed as inhibition of peak current by electrophysiology methodic500.3100uM
6-[2-(2-methyl-1-propan-2-yl-3,4-dihydro-1H-isoquinolin-7-yl)ethynyl]naphthalene-2-carboximidamide607550: Inhibition of ASIC3 assessed as inhibition of peak current by electrophysiology methodic500.4600uM
3-amino-N-(diaminomethylidene)-5-(3-phenylphenyl)pyrazine-2-carboxamide352717: Inhibition of ASIC3 assessed as inhibition of peak current by patch clamp electrophysiologyic500.4900uM
3-amino-6-chloro-N-(diaminomethylidene)-5-(naphthalen-2-ylamino)pyrazine-2-carboxamide352717: Inhibition of ASIC3 assessed as inhibition of peak current by patch clamp electrophysiologyic500.5100uM
5-[2-[2-(aminomethyl)-3-chloro-1-benzothiophen-6-yl]ethynyl]-N,N-diethyl-3,4-dihydro-2H-quinolin-1-amine607550: Inhibition of ASIC3 assessed as inhibition of peak current by electrophysiology methodic500.5100uM
3-amino-N-(diaminomethylidene)-5-(3-thiophen-3-ylphenyl)pyrazine-2-carboxamide352717: Inhibition of ASIC3 assessed as inhibition of peak current by patch clamp electrophysiologyic500.6400uM
[3-chloro-6-[2-(2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)ethynyl]-1-benzothiophen-2-yl]methanamine607550: Inhibition of ASIC3 assessed as inhibition of peak current by electrophysiology methodic500.6800uM
2-[3-(2-phenylethynyl)phenyl]pyridin-4-amine594904: Inhibition of human ASIC3 expressed in HEK293 cells assessed as inhibition of acid-evoked current by manual patch-clamp electrophysiology assayic501.2000uM
6-[6-(2-methylpiperidin-1-yl)-2-pyridinyl]-1,2,3,4-tetrahydroisoquinoline594904: Inhibition of human ASIC3 expressed in HEK293 cells assessed as inhibition of acid-evoked current by manual patch-clamp electrophysiology assayic501.7000uM
[3-chloro-6-[2-(5-pyrrolidin-1-yl-5,6,7,8-tetrahydronaphthalen-1-yl)ethynyl]-1-benzothiophen-2-yl]methanamine607550: Inhibition of ASIC3 assessed as inhibition of peak current by electrophysiology methodic502.5000uM
4-[3-(4-amino-2-pyridinyl)phenyl]but-3-yn-1-ol594904: Inhibition of human ASIC3 expressed in HEK293 cells assessed as inhibition of acid-evoked current by manual patch-clamp electrophysiology assayic502.6000uM
[3-chloro-6-(2-phenylethynyl)-1-benzothiophen-2-yl]methanamine607550: Inhibition of ASIC3 assessed as inhibition of peak current by electrophysiology methodic502.8000uM
6-[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroisoquinoline594904: Inhibition of human ASIC3 expressed in HEK293 cells assessed as inhibition of acid-evoked current by manual patch-clamp electrophysiology assayic503.1000uM
6-(3,5-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline594904: Inhibition of human ASIC3 expressed in HEK293 cells assessed as inhibition of acid-evoked current by manual patch-clamp electrophysiology assayic503.3000uM
3-chloro-6-(2-phenylethynyl)-1-benzothiophene-2-carboximidamide607550: Inhibition of ASIC3 assessed as inhibition of peak current by electrophysiology methodic503.4000uM
6-methyl-N-[4-(6-piperazin-1-yl-3-pyridinyl)phenyl]pyridin-2-amine594904: Inhibition of human ASIC3 expressed in HEK293 cells assessed as inhibition of acid-evoked current by manual patch-clamp electrophysiology assayic503.8000uM
1-[3-[2-[2-(aminomethyl)-3-chloro-1-benzothiophen-6-yl]ethynyl]phenyl]-N,N-dimethylethanamine607550: Inhibition of ASIC3 assessed as inhibition of peak current by electrophysiology methodic504.3000uM
Amiloride352717: Inhibition of ASIC3 assessed as inhibition of peak current by patch clamp electrophysiologyic504.4000uM
[6-(2-phenylethynyl)naphthalen-2-yl]methanamine607550: Inhibition of ASIC3 assessed as inhibition of peak current by electrophysiology methodic504.8000uM
2-phenyl-6-(pyridin-2-ylmethyl)pyridin-4-amine594904: Inhibition of human ASIC3 expressed in HEK293 cells assessed as inhibition of acid-evoked current by manual patch-clamp electrophysiology assayic505.8000uM
6-(2-phenylethynyl)naphthalene-2-carboximidamide607550: Inhibition of ASIC3 assessed as inhibition of peak current by electrophysiology methodic506.3000uM
2-phenylpyridin-4-amine594904: Inhibition of human ASIC3 expressed in HEK293 cells assessed as inhibition of acid-evoked current by manual patch-clamp electrophysiology assayic506.9000uM
6-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroisoquinoline594904: Inhibition of human ASIC3 expressed in HEK293 cells assessed as inhibition of acid-evoked current by manual patch-clamp electrophysiology assayic507.1000uM
N-(6-methyl-2-pyridinyl)furo[2,3-c]pyridin-7-amine594904: Inhibition of human ASIC3 expressed in HEK293 cells assessed as inhibition of acid-evoked current by manual patch-clamp electrophysiology assayic509.0000uM
4-amino-N-[2-(4-chlorophenyl)ethyl]-2-propylquinoline-6-carboxamide594904: Inhibition of human ASIC3 expressed in HEK293 cells assessed as inhibition of acid-evoked current by manual patch-clamp electrophysiology assayic509.6000uM

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

ChemicalActions (top 5)PubMed papers
aristolochic acid Iincreases expression1
triphenyl phosphateaffects expression1
tetramethylpyrazineincreases expression1
butyraldehydedecreases expression1
jinfukangaffects cotreatment, decreases expression1
2,3,5-trichloro-6-phenyl-(1,4)benzoquinonedecreases expression1
Sunitinibincreases expression1
Arsenicincreases methylation1
Benzo(a)pyreneaffects methylation1
Cisplatinaffects cotreatment, decreases expression1
Estradioldecreases expression1
Lovastatinincreases expression1
Silicon Dioxidedecreases expression1
Smokedecreases expression1
Thiramincreases expression1
Tobacco Smoke Pollutiondecreases expression1
Valproic Acidincreases methylation1
Gold Compoundsincreases expression1
Acrylamidedecreases expression1
S-Nitrosoglutathioneincreases expression1

ChEMBL screening assays

14 unique, capped per target: 14 binding

Representative assays (with source publication via chembl_document):

Assay IDTypeDescriptionSource paper
CHEMBL1060810BindingInhibition of ASIC3 at 1 uM by patch-clamp electrophysiology assay relative to baseline peak currentAmidine derived inhibitors of acid-sensing ion channel-3 (ASIC3). — Bioorg Med Chem Lett

Cellosaurus cell lines

2 cell lines: 1 spontaneously immortalized cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

CellosaurusNameCategorySex
CVCL_C0XTB’SYS CHO ASIC3Spontaneously immortalized cell lineFemale
CVCL_D1JCPrecisION hASIC3-HEKTransformed cell lineFemale

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.

About this page

Generated deterministically by Sugi Atlas from primary biomedical databases via BioBTree. Every record on this page traces to a primary source.

Generated
Atlas version
v1.1.2
BioBTree
v2.0.2

Sources 80

This page pulls from 80 datasets indexed by BioBTree:

alphafoldalphamissenseantibodybgeebgee_evidencebindingdbbiogrid_interactionbrendabrenda_kineticsccdscellosauruschembl_activitychembl_assaychembl_documentchembl_moleculechembl_targetciviccivic_evidenceclingen_dosageclingen_gene_validityclinical_trialsclinvarcollectrictd_gene_interactiondbsnpdepmapdiamond_similarityefoensemblentrezesm2_similarityexonfantom5_genefantom5_promotergenccgenerifgogoparentgtopdbgtopdb_interactiongwasgwas_studyhgnchpointactinterprointogenjasparmeshmimmirdbmondomsigdborphanetorthologparalogpatent_compoundpdbpfampharmgkb_clinicalpharmgkb_genepharmgkb_guidelinepharmgkb_variantpubchempubchem_activitypubchem_assaypubmedreactomereactomeparentrefseqrhearnacentralscxa_expressionscxa_gene_experimentsignorspliceaistring_interactiontranscriptufeatureuniprot