ASIC1

Summary

ASIC1 (acid sensing ion channel subunit 1, HGNC:100) is a protein-coding gene on chromosome 12q13.12, encoding Acid-sensing ion channel 1 (P78348). Forms voltage-independent, pH-gated trimeric sodium channels that act as postsynaptic excitatory receptors in the nervous system, playing a crucial role in regulating synaptic plasticity, learning, and memory.

This gene encodes a member of the acid-sensing ion channel (ASIC) family of proteins, which are part of the degenerin/epithelial sodium channel (DEG/ENaC) superfamily. Members of the ASIC family are sensitive to amiloride and function in neurotransmission. The encoded proteins function in learning, pain transduction, touch sensation, and development of memory and fear. Alternatively spliced transcript variants have been described.

Source: NCBI Gene 41 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 70 total
• Druggable target: yes
• MANE Select transcript: NM_001095

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:100
Approved symbol	ASIC1
Name	acid sensing ion channel subunit 1
Location	12q13.12
Locus type	gene with protein product
Status	Approved
Aliases	BNaC2, hBNaC2
Ensembl gene	ENSG00000110881
Ensembl biotype	protein_coding
OMIM	602866
Entrez	41

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 10 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000228468, ENST00000447966, ENST00000453327, ENST00000548350, ENST00000549792, ENST00000550558, ENST00000551199, ENST00000552438, ENST00000552633, ENST00000895671, ENST00000895672, ENST00000895673, ENST00000895674, ENST00000964545

RefSeq mRNA: 10 — MANE Select: NM_001095 NM_001095, NM_001256830, NM_001412756, NM_001412757, NM_001412758, NM_001412759, NM_001412760, NM_001412761, NM_001412762, NM_020039

CCDS: CCDS44876, CCDS58228, CCDS8796

Canonical transcript exons

ENST00000447966 — 12 exons

Exon	Start	End
ENSE00001520193	50057596	50057916
ENSE00001799436	50059759	50059954
ENSE00002239810	50058751	50059128
ENSE00003486452	50081260	50081364
ENSE00003493613	50077213	50077363
ENSE00003542246	50078924	50078980
ENSE00003594005	50080498	50080589
ENSE00003607728	50078000	50078127
ENSE00003634884	50081102	50081181
ENSE00003645423	50079902	50080055
ENSE00003668114	50078421	50078577
ENSE00003901093	50081545	50083611

Expression profiles

Bgee: expression breadth ubiquitous, 201 present calls, max score 92.75.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.2831 / max 56.0994, expressed in 1170 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
125401	3.1480	1158
125402	0.1351	68

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	92.75	gold quality
cortical plate	UBERON:0005343	92.56	gold quality
cerebellar hemisphere	UBERON:0002245	91.93	gold quality
cerebellar cortex	UBERON:0002129	91.76	gold quality
ganglionic eminence	UBERON:0004023	91.55	gold quality
putamen	UBERON:0001874	90.58	gold quality
caudate nucleus	UBERON:0001873	90.32	gold quality
cerebellum	UBERON:0002037	89.90	gold quality
nucleus accumbens	UBERON:0001882	89.63	gold quality
right frontal lobe	UBERON:0002810	89.18	gold quality
amygdala	UBERON:0001876	88.60	gold quality
hypothalamus	UBERON:0001898	87.83	gold quality
prefrontal cortex	UBERON:0000451	87.34	gold quality
Brodmann (1909) area 9	UBERON:0013540	86.36	gold quality
cingulate cortex	UBERON:0003027	86.06	gold quality
anterior cingulate cortex	UBERON:0009835	85.82	gold quality
telencephalon	UBERON:0001893	85.81	gold quality
substantia nigra	UBERON:0002038	85.42	gold quality
neocortex	UBERON:0001950	85.38	gold quality
frontal cortex	UBERON:0001870	85.24	gold quality
frontal lobe	UBERON:0016525	85.23	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	85.06	gold quality
Ammon’s horn	UBERON:0001954	84.98	gold quality
temporal lobe	UBERON:0001871	84.86	gold quality
cerebral cortex	UBERON:0000956	84.73	gold quality
ventricular zone	UBERON:0003053	84.65	gold quality
midbrain	UBERON:0001891	84.44	gold quality
brain	UBERON:0000955	84.26	gold quality
central nervous system	UBERON:0001017	84.15	gold quality
forebrain	UBERON:0001890	83.56	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ENAD-17	no	115.04
E-ANND-3	no	2.73

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

176 targeting ASIC1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4447	99.85	67.81	2900

Literature-anchored findings (GeneRIF, showing 40)

• Results examine the interactions of wild type and mutant forms of the gp41 helicase with the T4 gp59 helicase loader and gp32 single-stranded DNA binding proteins. (PMID:15740739)
• Data indicate that hexameric gp41 helicase binds weakly to the ss-dsDNA junction of a replication fork. (PMID:24062430)
• Gp59-DNA interactions are needed to load Gp41 onto nascent or collapsed replication forks lacking clusters of Gp32 and to coordinate bidirectional replication from T4 origins. (PMID:24338568)
• wild type CFTR elevates the acid-gated Na(+) current of ASIC1a/2a in part by altering the kinetics of extracellular Na(+) interaction. (PMID:11748227)
• participation of multiple PKC isotypes contributes to the overall activity of BNaC2 (PMID:12244121)
• ASICs are leading acid sensors in human nociceptors and VR1 participates in the nociception mainly under extremely acidic conditions. (PMID:12393854)
• ASIC1a and H(+)-gated currents may contribute to the development of abnormal fear and to anxiety disorders. (PMID:14988500)
• Ibuprofen studies show ASIC1a is a significant contributor to cutaneous acid-induced pain. (PMID:15574747)
• These observations strongly suggest the acid-induced current is mediated by ASIC1 channels. (PMID:15576453)
• expression of vanilloid receptor subtype-1 and acid-sensing ion channel genes in the human trigeminal ganglion neurons (PMID:15738111)
• Data found ACCN2 interact with ataxin-3 and provide new clues for the pathogenesis of spinocerebellar ataxia type 3 and Machado-Joseph disease (SCA3/MJD). (PMID:15952105)
• functional expression of ASICs is characteristic feature of adenoid cystic carcinomas cells (PMID:17324378)
• Sulfhydryl compounds potentiate H(+)-gated currents via two mechanisms, metal chelation and redox modulation of target amino acids. (PMID:17392378)
• Spontaneous currents represent activation of acid-sensitive ion channels (ASICs) by autocrine vesicular release of protons from HEK cells. (PMID:17443677)
• AKAP150 and the protein phosphatase calcineurin are binding proteins to ASIC2a, and calcineurin regulates ASIC1a and ASIC2a activity (PMID:17548344)
• endogenous peptides shift steady-state desensitization suggests that RF-amides could impact the role of ASIC1a in both pain and neuronal damage following stroke and ischemia. (PMID:17984098)
• A case-control twin study could not detect association of ACCN2 with genetic risk shared among human anxiety spectrum disorders. (PMID:18349698)
• Atomic force microscopy was used to image unprocessed ASIC1a bound to mica. (PMID:18514062)
• Data show that transfected ASIC4 is targeted to the plasma membrane in CHO-K1 cells, where it associates with ASIC1a and downregulates exogenous ASIC1a expression. (PMID:18662336)
• Patch-clamp photometry was used to determine the contribution of Ca(2+) to total current through native and recombinant ASIC1a receptors. (PMID:19185346)
• a significant inhibition of D54-MG cell migration after ASIC1, alphaENaC, or gammaENaC knockdown, consistent with the hypothesis that ENaC/Degenerin subunits play an important role in glioma cell biology. (PMID:19561078)
• Results indicate that specific regions play overlapping roles in pH-dependent gating and PcTx1-dependent modulation of ASIC1a activity, whereas a distinct region determines the calcium dependence of ASIC1a activation. (PMID:19654327)
• analysis of amiloride docking to acid-sensing ion channel-1 (PMID:20048170)
• The contact region between three domains of the extracellular loop of ASIC1a is critical for channel function. (PMID:20215117)
• functional homomeric ASIC1a channels are predominantly expressed in neurons from the human brain. (PMID:20216553)
• A combined computational and functional approach identifies new residues involved in pH-dependent gating of ASIC1a. (PMID:20299463)
• These results demonstrate for the first time the differential distribution of ASIC1 and ASIC2 in human rapidly adapting low-threshold mechanoreceptors, and suggest specific roles of both proteins in mechanotransduction. (PMID:20306292)
• analysis of a complex between the sigma-1 receptor and a target ion channel, analysis of the stoichiometry of the interaction as 1 sigma-1 receptor/1 ASIC1a subunit (PMID:20371317)
• matriptase is expressed in glioma cells and that matriptase specifically cleaves ASIC1 in heterologous expression systems. (PMID:20601429)
• analysis of the ASIC1a and ASIC1b calcium permeable human acid-sensing ion channel 1 transcript variants (PMID:21036899)
• Results indicate that PICK1 regulates trafficking and function of ASIC1a in a lipid binding-dependent manner. (PMID:21176140)
• These data suggest that different ENaC/ASIC1 subunits interact and could combine to form a hybrid channel that likely underlies the amiloride-sensitive current seen in human glioma cells. (PMID:21346156)
• The results of this study demonstrated for the first time an association between an ASC1a variant allele and TLE in a Han Chinese population. (PMID:21664108)
• 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)
• ASIC1a has two desensitized states with markedly different stabilities. (PMID:23048040)
• ASIC1a channels desensitize rapidly in the presence of a continuous acidosis or following a preexposure to minor pH drop, raising doubt for their contributions to the acidosis-mediated neuronal injury. (PMID:23224900)
• Regions of the extracellular palm domain and the beta(11-12) linker are important for inactivation and steady-state desensitization of ASIC1a. (PMID:23977127)
• results suggest that FPI induces cerebral acidosis that activates ASIC channels and contributes to secondary injury in TBI. They also suggest a therapeutic strategy to attenuate the adverse consequences of TBI (PMID:23991103)
• it can be concluded that CaMKII regulates the activity of ASIC1, which is associated with the ability of GBM cells to migrate. (PMID:24100685)
• Provide evidence for the roles of OGR1 and ASIC1a in the regulation of intestinal passive Mg(2+) absorption. (PMID:24375028)

Cross-species orthologs

27 orthologs

Organism	Symbol	Gene ID
danio_rerio	asic1a	ENSDARG00000008329
mus_musculus	Asic1	ENSMUSG00000023017
rattus_norvegicus	Asic1	ENSRNOG00000059765
drosophila_melanogaster	Nach	FBGN0024319
drosophila_melanogaster	ppk28	FBGN0030795
drosophila_melanogaster	ppk17	FBGN0032602
drosophila_melanogaster	ppk6	FBGN0034489
drosophila_melanogaster	ppk12	FBGN0034730
drosophila_melanogaster	ppk29	FBGN0034965
drosophila_melanogaster	ppk24	FBGN0039839
drosophila_melanogaster	ppk22	FBGN0051105
drosophila_melanogaster	ppk8	FBGN0052792
drosophila_melanogaster	ppk5	FBGN0053289
drosophila_melanogaster	ppk16	FBGN0065108
drosophila_melanogaster	ppk11	FBGN0065109
drosophila_melanogaster	ppk9	FBGN0085398
drosophila_melanogaster	ppk18	FBGN0265001
caenorhabditis_elegans		WBGENE00003168
caenorhabditis_elegans		WBGENE00003174
caenorhabditis_elegans		WBGENE00007518
caenorhabditis_elegans		WBGENE00009073
caenorhabditis_elegans		WBGENE00011891
caenorhabditis_elegans	delm-2	WBGENE00016063
caenorhabditis_elegans	acd-1	WBGENE00016064
caenorhabditis_elegans	acd-2	WBGENE00016066
caenorhabditis_elegans		WBGENE00016699
caenorhabditis_elegans		WBGENE00017879

Paralogs (8): ASIC4 (ENSG00000072182), ASIC2 (ENSG00000108684), SCNN1A (ENSG00000111319), SCNN1D (ENSG00000162572), SCNN1G (ENSG00000166828), SCNN1B (ENSG00000168447), ASIC3 (ENSG00000213199), ASIC5 (ENSG00000256394)

Protein

Protein identifiers

Acid-sensing ion channel 1 — P78348 (reviewed: P78348)

Alternative names: Amiloride-sensitive cation channel 2, neuronal, Brain sodium channel 2

All UniProt accessions (4): P78348, F8VSK4, H0YHD6, H7C1W9

UniProt curated annotations — full annotation on UniProt →

Function. Forms voltage-independent, pH-gated trimeric sodium channels that act as postsynaptic excitatory receptors in the nervous system, playing a crucial role in regulating synaptic plasticity, learning, and memory. Upon extracellular pH drop this channel elicits transient, fast activating, and completely desensitizing inward currents. Displays high selectivity for sodium ions but can also permit the permeation of other cations. Regulates more or less directly intracellular calcium concentration and CaMKII phosphorylation, and thereby the density of dendritic spines. Modulates neuronal activity in the circuits underlying innate fear. Has high selectivity for sodium ions, but can also be permeable to other cations including calcium, lithium and potassium. Produces acid activated currents with a reduced amplitude and inactivates faster. Has high selectivity for sodium ions but also supports a calcium-mediated current which is sustained and maintained as long as acidic conditions are present. Also potentially permeable to lithium and potassium. Has no measurable proton-gated sodium channel activity in vitro.

Subunit / interactions. Forms functional homotrimeric channels. Forms heterotrimers with other ASIC proteins, resulting in channels with distinct properties. Interacts with PICK1; regulates ASIC1 clustering in membranes. Interacts with STOM; alters heterotrimeric channels activity. Interacts with PCYOX1L; increases ion channel currents by increasing Asic1a surface expression.

Subcellular location. Cell membrane. Postsynaptic cell membrane. Cell projection. Dendrite Cell membrane.

Tissue specificity. Expressed in neurons throughout the central and peripheral nervous system.

Post-translational modifications. pH-gating could be regulated by serine proteases. Phosphorylation by PKA regulates interaction with PICK1 and subcellular localization. Phosphorylation by PKC may regulate the channel.

Activity regulation. Potentiated by FMRFamide-related neuropeptides, which are induced during inflammation and modulate pain responses. Inhibited by the diuretic drug amiloride. Spider venom psalmotoxin-1 inhibits the channel by locking it in its desensitized conformation. The homotrimeric channel is inhibited by the spider venom pi-theraphotoxin-Hm3a. Homotrimeric and heterotrimeric (with ASIC2 isoform 1) channels are inhibited by the snake venom mambalgin-1, which prevents proton-induced transitions from the resting closed state to the active and/or desensitized states. Inhibited by Texas coral snake toxin MitTx1.

Domain organisation. The second transmembrane domain (TM2) is a discontinuous alpha-helix disrupted by the GAS motif, which forms the selectivity filter by adopting an extended, belt-like conformation aligned approximately parallel to the membrane plane. This peptide belt encircles the waist of the channel and divides TM2 into two discontinuous helical segments. The distal helical segment of TM2 interacts with the cytoplasmic portion of the first transmembrane domain (TM1) from a neighboring subunit, contributing to the structural and functional integrity of the channel.

Similarity. Belongs to the amiloride-sensitive sodium channel (TC 1.A.6) family. ASIC1 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
P78348-2	Asic1a, hvariant 2	yes
P78348-1	1, hvariant 1
P78348-3	Asic1b, hvariant 3

RefSeq proteins (10): NP_001086, NP_001243759, NP_001399685, NP_001399686, NP_001399687, NP_001399688, NP_001399689, NP_001399690, NP_001399691, NP_064423 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001873	ENaC	Family
IPR004724	ENaC_chordates	Family
IPR020903	ENaC_CS	Conserved_site

Pfam: PF00858

Catalyzed reactions (Rhea), 4 shown:

• K(+)(in) = K(+)(out) (RHEA:29463)
• Ca(2+)(in) = Ca(2+)(out) (RHEA:29671)
• Na(+)(in) = Na(+)(out) (RHEA:34963)
• Li(+)(in) = Li(+)(out) (RHEA:78551)

UniProt features (72 total): helix 20, strand 15, mutagenesis site 10, disulfide bond 7, topological domain 3, turn 3, site 3, modified residue 2, glycosylation site 2, transmembrane region 2, splice variant 2, chain 1, sequence conflict 1, short sequence motif 1

Structure

Experimental structures (PDB)

16 structures.

PDB	Method	Resolution (Å)
9E4I	ELECTRON MICROSCOPY	2.33
9E4H	ELECTRON MICROSCOPY	2.61
9E4F	ELECTRON MICROSCOPY	2.69
9E4A	ELECTRON MICROSCOPY	2.74
9E4K	ELECTRON MICROSCOPY	2.77
9E4G	ELECTRON MICROSCOPY	2.8
6L6N	X-RAY DIFFRACTION	2.86
7RNN	ELECTRON MICROSCOPY	2.86
9E4J	ELECTRON MICROSCOPY	2.87
9E4B	ELECTRON MICROSCOPY	3.09
9E4E	ELECTRON MICROSCOPY	3.16
9E4D	ELECTRON MICROSCOPY	3.19
6L6I	X-RAY DIFFRACTION	3.24
9E4C	ELECTRON MICROSCOPY	3.41
7CFS	ELECTRON MICROSCOPY	3.56
7CFT	ELECTRON MICROSCOPY	3.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P78348-F1	84.12	0.61

Antibody-complex structures (SAbDab): 1 — 7RNN

Functional residue map

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

Catalytic / active sites (3): 79 (involved in channel desensitization; the process by which the channel becomes unresponsive to proton stimulation); 352 (involved in the inhibition by the spider venom psalmotoxin-1); 357 (involved in proton-dependent gating)

Post-translational modifications (2): 479, 499

Disulfide bonds (7): 93–194, 172–179, 290–367, 310–363, 314–361, 323–345, 325–337

Glycosylation sites (2): 368, 395

Mutagenesis-validated functional residues (10):

Position	Phenotype
102	decreased inhibition by mambalgin-1; when associated with e-167.
155	decreased inhibition by mambalgin-1.
167	decreased inhibition by mambalgin-1; when associated with r-102.
347	loss of inhibition by mambalgin-1. changed ph-gating as lower ph is required for activation.
351	decreased inhibition by mambalgin-1. changed ph-gating as lower ph is required for activation.
352	complete loss in the shift of ph for both activation and desensitization by the spider venom psalmotoxin-1. decreased in
357	changed ph-gating as lower ph is required for activation.
360	loss of inhibition by mambalgin-1.
478	no effect on phosphorylation.
479	loss of phosphorylation.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

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

MSigDB gene sets: 250 (showing top): GOBP_MEMORY, TGGTGCT_MIR29A_MIR29B_MIR29C, AGGAAGC_MIR5163P, RRAGTTGT_UNKNOWN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, BENPORATH_ES_WITH_H3K27ME3, GOBP_COGNITION, GOBP_BEHAVIOR, GOBP_RESPONSE_TO_AMINE, GOBP_SYNAPSE_ASSEMBLY, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, CMYB_01, GOBP_ASSOCIATIVE_LEARNING, GOCC_CELL_SURFACE, GOBP_SENSORY_PERCEPTION_OF_CHEMICAL_STIMULUS

GO Biological Process (20): behavioral fear response (GO:0001662), response to amphetamine (GO:0001975), sodium ion transport (GO:0006814), neurotransmitter secretion (GO:0007269), memory (GO:0007613), associative learning (GO:0008306), response to acidic pH (GO:0010447), sodium ion transmembrane transport (GO:0035725), regulation of membrane potential (GO:0042391), negative regulation of neurotransmitter secretion (GO:0046929), sensory perception of sour taste (GO:0050915), calcium ion transmembrane transport (GO:0070588), cellular response to pH (GO:0071467), regulation of postsynapse assembly (GO:0150052), monoatomic ion transport (GO:0006811), monoatomic cation transport (GO:0006812), calcium ion transport (GO:0006816), monoatomic ion transmembrane transport (GO:0034220), establishment of localization in cell (GO:0051649), obsolete inorganic cation transmembrane transport (GO:0098662)

GO Molecular Function (9): ligand-gated sodium channel activity (GO:0015280), monoatomic ion-gated channel activity (GO:0022839), pH-gated monoatomic ion channel activity (GO:0160128), monoatomic ion channel activity (GO:0005216), monoatomic cation channel activity (GO:0005261), sodium channel activity (GO:0005272), protein binding (GO:0005515), ligand-gated monoatomic ion channel activity (GO:0015276), obsolete inorganic cation transmembrane transporter activity (GO:0022890)

GO Cellular Component (11): Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), cell surface (GO:0009986), dendrite (GO:0030425), presynapse (GO:0098793), postsynaptic density membrane (GO:0098839), glutamatergic synapse (GO:0098978), membrane (GO:0016020), cell projection (GO:0042995), synapse (GO:0045202), postsynaptic membrane (GO:0045211)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Ion channel transport	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
metal ion transport	2
response to pH	2
monoatomic cation transmembrane transport	2
monoatomic ion transport	2
ligand-gated channel activity	2
monoatomic ion channel activity	2
synapse	2
behavioral defense response	1
fear response	1
response to amine	1
neurotransmitter transport	1
chemical synaptic transmission	1
establishment of localization in cell	1
presynapse	1
signal release from synapse	1
learning or memory	1
learning	1
sodium ion transport	1
monoatomic ion transmembrane transport	1
regulation of biological quality	1
neurotransmitter secretion	1
regulation of neurotransmitter secretion	1
negative regulation of neurotransmitter transport	1
negative regulation of secretion by cell	1
sensory perception of taste	1
calcium ion transport	1
cellular response to abiotic stimulus	1
regulation of synapse assembly	1
postsynapse assembly	1
regulation of postsynapse organization	1
transport	1
transmembrane transport	1
establishment of localization	1
cellular localization	1
sodium channel activity	1
ligand-gated monoatomic cation channel activity	1
ligand-gated monoatomic ion channel activity	1
monoatomic ion transmembrane transporter activity	1
channel activity	1

Protein interactions and networks

STRING

816 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ASIC1	ASIC2	Q16515	907
ASIC1	P2RX4	Q99571	753
ASIC1	UBE2G1	P62253	743
ASIC1	SGK3	Q96BR1	707
ASIC1	TRPV1	Q8NER1	623
ASIC1	PICK1	Q9NRD5	570
ASIC1	SCNN1A	P37088	549
ASIC1	SGK1	O00141	508
ASIC1	SCNN1G	P51170	508
ASIC1	TRPA1	O75762	502
ASIC1	CAMK2A	Q9UQM7	493
ASIC1	SYVN1	Q86TM6	490
ASIC1	PIEZO2	Q9H5I5	483
ASIC1	TRPV4	Q9HBA0	476
ASIC1	ITGB1	P05556	471

IntAct

47 interactions, top by confidence:

A	B	Type	Score
ASIC1	PICK1	psi-mi:“MI:0915”(physical association)	0.660
PICK1	ASIC1	psi-mi:“MI:0915”(physical association)	0.660
PICK1	ASIC1	psi-mi:“MI:0403”(colocalization)	0.660
ASIC1	KIR3DL3	psi-mi:“MI:0915”(physical association)	0.560
ASIC1	MGST2	psi-mi:“MI:0915”(physical association)	0.560
DPEP1	ILVBL	psi-mi:“MI:0914”(association)	0.530
PICK1	ILVBL	psi-mi:“MI:0914”(association)	0.530
NCEH1	CLGN	psi-mi:“MI:0914”(association)	0.530
ANKH	FAM234B	psi-mi:“MI:0914”(association)	0.530
CACNA1C	DISP2	psi-mi:“MI:0914”(association)	0.350
HCN1	POTEF	psi-mi:“MI:0914”(association)	0.350
CANX	HLA-A	psi-mi:“MI:0914”(association)	0.350
TCTN2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
TMPRSS11B	ADAM10	psi-mi:“MI:0914”(association)	0.350
ASIC1	TNFRSF10B	psi-mi:“MI:0914”(association)	0.350
C15orf32	NPC1	psi-mi:“MI:0914”(association)	0.350
MBLAC2	CD63	psi-mi:“MI:0914”(association)	0.350
GP9	ESYT2	psi-mi:“MI:0914”(association)	0.350
APOM	ESYT2	psi-mi:“MI:0914”(association)	0.350
HLA-C	TMEM131L	psi-mi:“MI:0914”(association)	0.350
DUOXA2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
UPK2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
SFTPC	TMEM131L	psi-mi:“MI:0914”(association)	0.350
HLA-DRB3	TMEM131L	psi-mi:“MI:0914”(association)	0.350
P2RX2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
ASIC4	TMEM131L	psi-mi:“MI:0914”(association)	0.350
ASIC1		psi-mi:“MI:0914”(association)	0.350

BioGRID (81): ASIC1 (Affinity Capture-Western), ASIC1 (Proximity Label-MS), ASIC2 (Affinity Capture-MS), TNFRSF10B (Affinity Capture-MS), SLC27A3 (Affinity Capture-MS), UFSP2 (Affinity Capture-MS), ASIC1 (Affinity Capture-MS), EIF2AK3 (Affinity Capture-MS), HMOX2 (Affinity Capture-MS), ASIC1 (Biochemical Activity), PICK1 (Affinity Capture-Western), ASIC1 (Two-hybrid), KIR3DL3 (Two-hybrid), ASIC1 (Proximity Label-MS), ASIC1 (Proximity Label-MS)

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: A5D7U4, F1MJW3, H1AFJ5, H1AFJ6, H1AFJ7, H2Q5A1, H2QAR5, H2QAR6, H9GBX2, K7FQW8, K7FSQ4, K7GET2, O13262, O13263, O46547, O62816, O97741, O97742, P24612, P37088, P37089, P37090, P37091, P51167, P51168, P51169, P51170, P51171, P51172, P55270, P55926, P78348, Q09274, Q17298, Q28738, Q61180, Q708S6, Q92075, Q95165, Q9R1N2

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
PRKACA	unknown	ASIC1	phosphorylation
PICK1	“up-regulates activity”	ASIC1	relocalization

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	56
Likely benign	2
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

1883 predictions. Top by Δscore:

Variant	Effect	Δscore
12:50057915:AGGT:A	donor_loss	1.0000
12:50057916:GG:G	donor_loss	1.0000
12:50057917:G:T	donor_loss	1.0000
12:50058747:CCA:C	acceptor_loss	1.0000
12:50058748:CA:C	acceptor_loss	1.0000
12:50058749:A:AC	acceptor_loss	1.0000
12:50058749:A:AG	acceptor_gain	1.0000
12:50058749:AG:A	acceptor_gain	1.0000
12:50058750:G:GG	acceptor_gain	1.0000
12:50058750:G:GT	acceptor_loss	1.0000
12:50058750:GG:G	acceptor_gain	1.0000
12:50058750:GGATC:G	acceptor_gain	1.0000
12:50059125:ACAGG:A	donor_loss	1.0000
12:50059126:CAGG:C	donor_loss	1.0000
12:50059128:GGT:G	donor_loss	1.0000
12:50059130:T:A	donor_loss	1.0000
12:50059750:G:A	acceptor_gain	1.0000
12:50059758:G:GC	acceptor_loss	1.0000
12:50059950:AGGTG:A	donor_gain	1.0000
12:50059951:GGTGG:G	donor_gain	1.0000
12:50059952:GTG:G	donor_gain	1.0000
12:50077207:C:CA	acceptor_gain	1.0000
12:50077211:A:AG	acceptor_gain	1.0000
12:50077212:G:GG	acceptor_gain	1.0000
12:50077333:G:GT	donor_gain	1.0000
12:50077359:GACTG:G	donor_gain	1.0000
12:50077361:CTGG:C	donor_loss	1.0000
12:50077364:G:GA	donor_loss	1.0000
12:50077365:T:G	donor_loss	1.0000
12:50077999:GACGA:G	acceptor_gain	1.0000

AlphaMissense

3495 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:50077236:C:G	C194W	1.000
12:50078550:T:A	C323S	1.000
12:50078550:T:C	C323R	1.000
12:50078551:G:A	C323Y	1.000
12:50078551:G:C	C323S	1.000
12:50078551:G:T	C323F	1.000
12:50078552:C:G	C323W	1.000
12:50078556:T:A	C325S	1.000
12:50078556:T:C	C325R	1.000
12:50078557:G:A	C325Y	1.000
12:50078557:G:C	C325S	1.000
12:50078558:C:G	C325W	1.000
12:50078938:T:A	C337S	1.000
12:50078938:T:C	C337R	1.000
12:50078939:G:A	C337Y	1.000
12:50078939:G:C	C337S	1.000
12:50078939:G:T	C337F	1.000
12:50078940:T:G	C337W	1.000
12:50078962:T:A	C345S	1.000
12:50078963:G:C	C345S	1.000
12:50081122:G:A	G440R	1.000
12:50081122:G:C	G440R	1.000
12:50081126:T:C	L441P	1.000
12:50081135:G:A	G444E	1.000
12:50081140:A:C	S446R	1.000
12:50081142:C:A	S446R	1.000
12:50081142:C:G	S446R	1.000
12:50058902:T:A	W46R	0.999
12:50058902:T:C	W46R	0.999
12:50059043:T:A	C93S	0.999

dbSNP variants (sampled 300 via entrez): RS1000134173 (12:50072337 C>G), RS1000152524 (12:50081246 C>G,T), RS1000212152 (12:50065258 C>A), RS1000268822 (12:50072092 A>C), RS1000404668 (12:50056277 C>G,T), RS1000606195 (12:50073313 A>G), RS1000640908 (12:50063138 G>T), RS1000712339 (12:50070133 G>A), RS1000923131 (12:50060217 G>A), RS1000956175 (12:50066901 A>T), RS1000987433 (12:50076190 G>T), RS1001055402 (12:50059944 A>G), RS1001087229 (12:50067138 G>T), RS1001535319 (12:50069097 C>A), RS1001622284 (12:50062140 T>A)

Disease associations

OMIM: gene MIM:602866 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST007293_76	Body fat distribution (arm fat ratio)	4.000000e-07
GCST007294_123	Body fat distribution (trunk fat ratio)	2.000000e-09
GCST007294_2	Body fat distribution (trunk fat ratio)	1.000000e-18
GCST007295_152	Body fat distribution (leg fat ratio)	4.000000e-13

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004341	body fat distribution

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1628477 (SINGLE PROTEIN)

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 (23 total), top 23:

Ligand	Action	Affinity	Parameter
[125I]psalmotoxin 1		9.7	pKd
Pi-hexatoxin-Hi1a	Channel blocker	9.3	pIC50
psalmotoxin 1	Channel blocker	9.0	pIC50
Pi-theraphotoxin-Hm3a	Channel blocker	8.5	pIC50
Zn2+	Channel blocker	8.2	pIC50
JNJ-799760	Channel blocker	7.6	pIC50
JNJ-67869386	Channel blocker	7.5	pIC50
ASC06-IgG1	Inhibition	7.1	pIC50
6-iodoamiloride	Channel blocker	7.1	pIC50
mambalgin-1	Channel blocker	7.0	pIC50
diminazene	Channel blocker	6.5	pIC50
NS383	Channel blocker	6.4	pIC50
compound 3b [PMID: 34097384]	Channel blocker	6.4	pIC50
H+	Activator	6.2	pEC50
A-317567	Channel blocker	5.7	pIC50
Pb2+	Channel blocker	5.4	pIC50
compound 5b [PMID: 25974655]	Channel blocker	5.2	pIC50
benzamil	Channel blocker	5.0	pIC50
ethylisopropylamiloride	Channel blocker	5.0	pIC50
nafamostat	Channel blocker	4.9	pIC50
amiloride	Channel blocker	4.68	pIC50
ibuprofen	Channel blocker	3.5	pIC50
flurbiprofen	Channel blocker	3.5	pIC50

ChEMBL bioactivities

14 potent at pChembl≥5 of 14 total, top 14 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.56	IC50	27.35	nM	CHEMBL3577296
6.65	IC50	224	nM	CHEMBL1800430
6.39	IC50	407	nM	CHEMBL5269133
6.29	IC50	518	nM	CHEMBL5270983
6.14	IC50	729	nM	CHEMBL5289168
6.01	IC50	972	nM	CHEMBL5278611
5.85	IC50	1420	nM	CHEMBL5287933
5.70	IC50	1990	nM	CHEMBL5285672
5.70	IC50	1990	nM	CHEMBL5291421
5.59	IC50	2590	nM	CHEMBL5267130
5.53	IC50	2948	nM	CHEMBL5276647
5.50	IC50	3140	nM	CHEMBL5267106
5.13	IC50	7340	nM	CHEMBL3577296
5.02	IC50	9538	nM	CHEMBL5283083

PubChem BioAssay actives

14 with measured affinity, of 57 total; 13 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
7-[(4-chlorophenyl)methyl-[2-(diethylamino)ethyl]amino]-2-oxochromene-3-carboximidamide	1226989: Inhibition of human ASIC1a endogenously expressed in HEK293 cells clamped at -100 mV gated ionic current at pH 6.7 by standard whole cell patch clamp assay	ic50	0.0273	uM
[3-chloro-6-[2-(1,2,3,4-tetrahydroisoquinolin-7-yl)ethynyl]-1-benzothiophen-2-yl]methanamine	607551: Inhibition of ASIC1a	ic50	0.2240	uM
2-[(Z)-[4-[3-[4-[(E)-(diaminomethylidenehydrazinylidene)methyl]phenyl]phenyl]phenyl]methylideneamino]guanidine;hydrochloride	1924622: Inhibition of human ASIC1a in HEK293 cells assessed as inward proton-gated current at pH 6.0 incubated with compound followed by PcTx1 addition by patch-clamp electrophysiology	ic50	0.4070	uM
2-[(E)-[4-[3-[4-[(E)-(diaminomethylidenehydrazinylidene)methyl]phenyl]-1-[(4-methoxyphenyl)methyl]pyrazol-5-yl]phenyl]methylideneamino]guanidine;bis(2,2,2-trifluoroacetic acid)	1924622: Inhibition of human ASIC1a in HEK293 cells assessed as inward proton-gated current at pH 6.0 incubated with compound followed by PcTx1 addition by patch-clamp electrophysiology	ic50	0.5180	uM
2-[(Z)-[4-[3-[4-[(Z)-(diaminomethylidenehydrazinylidene)methyl]phenyl]-1H-pyrazol-5-yl]phenyl]methylideneamino]guanidine;dihydrochloride	1924622: Inhibition of human ASIC1a in HEK293 cells assessed as inward proton-gated current at pH 6.0 incubated with compound followed by PcTx1 addition by patch-clamp electrophysiology	ic50	0.7290	uM
N-[(E)-[4-[3-[4-[(Z)-(4,5-dihydro-1H-imidazol-2-ylhydrazinylidene)methyl]phenyl]-1H-pyrazol-5-yl]phenyl]methylideneamino]-4,5-dihydro-1H-imidazol-2-amine;dihydrobromide	1924622: Inhibition of human ASIC1a in HEK293 cells assessed as inward proton-gated current at pH 6.0 incubated with compound followed by PcTx1 addition by patch-clamp electrophysiology	ic50	0.9720	uM
2-[(E)-[4-[3-[4-[(E)-(diaminomethylidenehydrazinylidene)methyl]phenyl]-1-methylpyrazol-5-yl]phenyl]methylideneamino]guanidine;bis(2,2,2-trifluoroacetic acid)	1924622: Inhibition of human ASIC1a in HEK293 cells assessed as inward proton-gated current at pH 6.0 incubated with compound followed by PcTx1 addition by patch-clamp electrophysiology	ic50	1.4200	uM
2-[(E)-[4-[5-(4-bromophenyl)-1H-pyrazol-3-yl]phenyl]methylideneamino]guanidine	1924622: Inhibition of human ASIC1a in HEK293 cells assessed as inward proton-gated current at pH 6.0 incubated with compound followed by PcTx1 addition by patch-clamp electrophysiology	ic50	1.9900	uM
2-[(E)-[4-[3-(4-fluorophenyl)-1-[(4-methoxyphenyl)methyl]pyrazol-5-yl]phenyl]methylideneamino]guanidine;2,2,2-trifluoroacetic acid	1924622: Inhibition of human ASIC1a in HEK293 cells assessed as inward proton-gated current at pH 6.0 incubated with compound followed by PcTx1 addition by patch-clamp electrophysiology	ic50	1.9900	uM
2-[(E)-[4-[5-(4-fluorophenyl)-1H-pyrazol-3-yl]phenyl]methylideneamino]guanidine;2,2,2-trifluoroacetic acid	1924622: Inhibition of human ASIC1a in HEK293 cells assessed as inward proton-gated current at pH 6.0 incubated with compound followed by PcTx1 addition by patch-clamp electrophysiology	ic50	2.5900	uM
2-[(E)-[4-[3-(4-tert-butylphenyl)phenyl]phenyl]methylideneamino]guanidine	1924622: Inhibition of human ASIC1a in HEK293 cells assessed as inward proton-gated current at pH 6.0 incubated with compound followed by PcTx1 addition by patch-clamp electrophysiology	ic50	2.9480	uM
2-[(E)-[4-[3-(4-fluorophenyl)-1-methylpyrazol-5-yl]phenyl]methylideneamino]guanidine;2,2,2-trifluoroacetic acid	1924622: Inhibition of human ASIC1a in HEK293 cells assessed as inward proton-gated current at pH 6.0 incubated with compound followed by PcTx1 addition by patch-clamp electrophysiology	ic50	3.1400	uM
2-[(E)-[4-[5-(4-fluorophenyl)-1,2-oxazol-3-yl]phenyl]methylideneamino]guanidine;hydrochloride	1924622: Inhibition of human ASIC1a in HEK293 cells assessed as inward proton-gated current at pH 6.0 incubated with compound followed by PcTx1 addition by patch-clamp electrophysiology	ic50	9.5380	uM

CTD chemical–gene interactions

40 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tretinoin	increases expression, decreases expression	3
mercuric bromide	decreases expression, affects cotreatment	2
entinostat	decreases expression, affects cotreatment	2
Cisplatin	affects cotreatment, increases expression, decreases expression	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
bisphenol A	decreases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
manganese chloride	increases abundance, affects cotreatment, decreases expression	1
ochratoxin A	increases acetylation, increases expression	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, increases expression	1
NSC 689534	affects binding, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	decreases expression	1
Panobinostat	decreases expression, affects cotreatment	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Benzo(a)pyrene	decreases expression	1
Cadmium	increases abundance, increases expression	1
Copper	affects binding, decreases expression	1

ChEMBL screening assays

32 unique, capped per target: 32 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1804677	Binding	Inhibition of ASIC1a	Identification of non-amidine inhibitors of acid-sensing ion channel-3 (ASIC3). — Bioorg Med Chem Lett

Cellosaurus cell lines

3 cell lines: 2 spontaneously immortalized cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C0XR	B’SYS CHO ASIC1a	Spontaneously immortalized cell line	Female
CVCL_C0XS	B’SYS CHO ASIC1b	Spontaneously immortalized cell line	Female
CVCL_SD63	HAP1 ASIC1 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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