KCNQ4

Summary

KCNQ4 (potassium voltage-gated channel subfamily Q member 4, HGNC:6298) is a protein-coding gene on chromosome 1p34.2, encoding Potassium voltage-gated channel subfamily KQT member 4 (P56696). Pore-forming subunit of the voltage-gated potassium (Kv) channel involved in the regulation of sensory cells excitability in the cochlea.

The protein encoded by this gene forms a potassium channel that is thought to play a critical role in the regulation of neuronal excitability, particularly in sensory cells of the cochlea. The current generated by this channel is inhibited by M1 muscarinic acetylcholine receptors and activated by retigabine, a novel anti-convulsant drug. The encoded protein can form a homomultimeric potassium channel or possibly a heteromultimeric channel in association with the protein encoded by the KCNQ3 gene. Defects in this gene are a cause of nonsyndromic sensorineural deafness type 2 (DFNA2), an autosomal dominant form of progressive hearing loss. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 9132 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nonsyndromic genetic hearing loss (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 72
• Clinical variants (ClinVar): 525 total — 24 pathogenic, 25 likely-pathogenic
• Phenotypes (HPO): 4
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_004700

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6298
Approved symbol	KCNQ4
Name	potassium voltage-gated channel subfamily Q member 4
Location	1p34.2
Locus type	gene with protein product
Status	Approved
Aliases	Kv7.4
Ensembl gene	ENSG00000117013
Ensembl biotype	protein_coding
OMIM	603537
Entrez	9132

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 5 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000347132, ENST00000443478, ENST00000506017, ENST00000509682, ENST00000967337, ENST00000967338

RefSeq mRNA: 2 — MANE Select: NM_004700 NM_004700, NM_172163

CCDS: CCDS456

Canonical transcript exons

ENST00000347132 — 14 exons

Exon	Start	End
ENSE00000768601	40818164	40818290
ENSE00000768602	40817265	40817355
ENSE00001230627	40783787	40784407
ENSE00001677156	40818505	40818680
ENSE00001824113	40838311	40840452
ENSE00003473809	40820165	40820260
ENSE00003493713	40819875	40819985
ENSE00003539830	40822314	40822402
ENSE00003555525	40833014	40833113
ENSE00003579961	40819347	40819472
ENSE00003583019	40837665	40837794
ENSE00003602206	40831084	40831304
ENSE00003633296	40824097	40824258
ENSE00003659616	40834967	40835098

Expression profiles

Bgee: expression breadth ubiquitous, 182 present calls, max score 94.14.

FANTOM5 (CAGE): breadth broad, TPM avg 0.9609 / max 57.3790, expressed in 414 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
2406	0.3409	183
2407	0.3290	185
2410	0.1244	57
2409	0.0920	31
2408	0.0401	11
201486	0.0345	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pigmented layer of retina	UBERON:0001782	94.14	gold quality
lower esophagus muscularis layer	UBERON:0035833	86.42	gold quality
lower esophagus	UBERON:0013473	86.36	gold quality
muscle layer of sigmoid colon	UBERON:0035805	86.30	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	84.94	gold quality
right coronary artery	UBERON:0001625	84.38	gold quality
mucosa of stomach	UBERON:0001199	84.28	gold quality
parotid gland	UBERON:0001831	84.15	silver quality
popliteal artery	UBERON:0002250	82.89	gold quality
tibial artery	UBERON:0007610	82.86	gold quality
aorta	UBERON:0000947	81.83	gold quality
ascending aorta	UBERON:0001496	80.63	gold quality
thoracic aorta	UBERON:0001515	80.63	gold quality
left coronary artery	UBERON:0001626	80.60	gold quality
coronary artery	UBERON:0001621	80.35	gold quality
gastrocnemius	UBERON:0001388	79.84	gold quality
hindlimb stylopod muscle	UBERON:0004252	79.73	gold quality
descending thoracic aorta	UBERON:0002345	79.41	gold quality
left uterine tube	UBERON:0001303	79.19	gold quality
body of uterus	UBERON:0009853	78.63	gold quality
muscle of leg	UBERON:0001383	78.03	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.53	gold quality
right frontal lobe	UBERON:0002810	76.94	gold quality
seminal vesicle	UBERON:0000998	76.20	silver quality
right hemisphere of cerebellum	UBERON:0014890	76.11	gold quality
esophagus	UBERON:0001043	76.08	gold quality
transverse colon	UBERON:0001157	75.80	gold quality
apex of heart	UBERON:0002098	75.70	gold quality
right uterine tube	UBERON:0001302	75.28	gold quality
colon	UBERON:0001155	75.20	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	2.58
E-MTAB-9543	no	1.22

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYCL, THRA

miRNA regulators (miRDB)

130 targeting KCNQ4, 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-6127	100.00	66.76	2188
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4514	99.99	67.10	1870
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-8082	99.95	67.27	1170

Literature-anchored findings (GeneRIF, showing 40)

• The W276S mutation has occurred three times independently, and most likely represents a hot spot for mutation in the KCNQ4 gene. (PMID:12112653)
• DFNA2 locus was found to be related to hereditary sensorineural hearing loss. (PMID:12484650)
• KCNQ3 interacts with KCNQ4. . A chimaera (KCNQ1-sid(Q3)) carrying the si domain of KCNQ3 within the KCNQ1 backbone interacted with KCNQ4. (PMID:12524525)
• Src associates with KCNQ2-5 subunits but phosphorylates only KCNQ3-5. (PMID:15304482)
• KCNQ4 phosphorylation via PKA and coupling to a complex that may include prestin can lead to the negative activation and the negative resting potential found in adult outer hair cells. (PMID:15660259)
• Polymorphisms within the KCNQ4 gene are associated with susceptibility Noise-induced hearing loss. (PMID:16823764)
• Results shows KCNQ4 SNPs were significantly associated with Age-related hearing impairment. (PMID:16917933)
• a novel mutation of KCNQ4 gene was identified in patients with nonsyndromic deafness. (PMID:17033161)
• In conclusion, this work demonstrates that inactivation is a key regulatory mechanism of Kv7.4 and Kv7.5 channels. (PMID:17237198)
• high-resolution structure of the Kv7.4 A-domain Tail together with biochemical experiments show that the domain is a self-assembling, parallel, four-stranded coiled coil (PMID:17329207)
• G296S mutant exerts a strong dominant-negative effect on potassium currents by reducing the wild type KCNQ4 channel expression at the cell surface (PMID:18030493)
• among the allowed assembly conformations are KCNQ3/4 and KCNQ4/5 heteromers. (PMID:18786918)
• KCNQ4 mutations associated with progressive sensorineural hearing loss. (PMID:18797286)
• Two novel missense mutations and a stop mutation were detected in three American families predicted to have DFNA2-related deafness; The latter is the first DFNA2-causing stop mutation reported in KCNQ4. (PMID:18941426)
• evidence of the cellular etiology and mechanisms of SGN degeneration in DFNA2. (PMID:20739290)
• Identified is novel mutation (c.664_681del) in KCNQ4 associated with hearing loss in a Korean family with dominantly inherited deafness. (PMID:20832469)
• mutations in the pore region, namely L274H, W276S, L281S, G285C, and G296S, as well as the C-terminal mutant G321S in the heterologous expression system, yielded non-functional channels because of endoplasmic reticulum retention of the mutant channels (PMID:20966080)
• Autosomal dominant progressive sensorineural hearing loss due to a novel mutation in the KCNQ4 gene. (PMID:21242547)
• no sequence alterations that segregate with autosomal dominant non-syndromic deafness in either GJB3 or KCNQ4 (PMID:21651318)
• Data show that KCNQ4 and KCNE1 isoforms were suppressed in placentas from term preeclamptic women. (PMID:21730298)
• This work describes a gene mutation that modulates touch sensitivity in mice and humans and establishes KCNQ4 as a specific molecular marker for rapidly adapting Meissner and a subset of hair follicle afferents. (PMID:22101641)
• Data indicate a missense mutation encoding a Tyr270His located at the N-terminus of the highly conserved of KCNQ4 pore helix sequence. (PMID:22420747)
• The present study supports the idea that a non-truncating mutation around the N-terminus of KCNQ4 pore helix may be related to moderate hearing loss. (PMID:23399560)
• KCNQ4 surface expression was restored by HSP90beta in cells mimicking heterozygous conditions of the DFNA2 patients. (PMID:23431407)
• In-frame deletion in KCNQ4 P-loop was identified in family members with autosomal dominant sensorineural hearing loss. (PMID:23443030)
• The data of this study identified a dynamic redox sensor within neuronal M-channels, which mediates reciprocal regulation of channel activity by NO and ROS (PMID:23554485)
• A new typical audiogram configuration characterized by mid-frequency predominant hearing loss caused by the KCNQ4 V230E mutation. (PMID:23717403)
• decreased cell surface expression and impaired conductance of the KCNQ4 channel are two mechanisms underlying hearing loss in DFNA2 (PMID:23750663)
• Differential protein kinase C-dependent modulation of Kv7.4 and Kv7.5 subunits of vascular Kv7 channels. (PMID:24297175)
• Identified the c.211delC mutation in the KCNQ4 gene and the c.2967C>A (p.H989Q) mutation in the TECTA gene to be associated with high-frequency sensorineural hearing loss in a Japanese family. (PMID:24655070)
• Kv7.4 currents are inhibited in a CB1 pathway repressed by endocannabinoid 2-AG (PMID:24927567)
• The study identified a novel KCNQ4 mutation in a five generation Chinese family and a known KCNQ4 mutation in a six generation Chinese family. (PMID:25116015)
• These findings suggest a protective role for Kv7.4 channels in the pulmonary circulation, limiting its reactivity to pressor agents and preventing hypoxia-induced pulmonary hypertension. (PMID:25361569)
• This study provides evidence that mouse Kv7 channels may contribute differently to regulating the functional properties of cerebral and coronary arteries. (PMID:25476662)
• Interaction between G-protein betagamma subunits and Kv7.4 is crucial for channel responses to membrane voltage. (PMID:25941381)
• genotype-phenotype correlation is analogous to that in KCNQ1 which causes autosomal dominant hereditary long QT syndrome 1 with milder phenotype and the autosomal recessive Jervell and Lange-Nielsen syndrome 1 with more severe phenotype (PMID:26036578)
• analysis of mechanistic insights into the critical roles of Ca(2+)/CaM regulation of the Kv7.4 channel under physiological and pathological conditions (PMID:26515070)
• Kv7.4 channels are present and functional in cardiac mitochondria; their activation exerts a significant cardioprotective role (PMID:26718475)
• Tannic acid activates Kv7.4 and Kv7.3/7.5 K(+) channels resulting in vasodilation. (PMID:26969140)
• Gene and protein expression analyses show the predominance of KV7.4 channels over the other KV7 channel subtypes in human detrusor. (PMID:27761601)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	kcnq4	ENSDARG00000089490
mus_musculus	Kcnq4	ENSMUSG00000028631
rattus_norvegicus	Kcnq4	ENSRNOG00000060435

Paralogs (31): KCNG1 (ENSG00000026559), KCNQ1 (ENSG00000053918), KCNQ2 (ENSG00000075043), KCND1 (ENSG00000102057), KCNA7 (ENSG00000104848), KCNA1 (ENSG00000111262), KCNC4 (ENSG00000116396), KCNS1 (ENSG00000124134), KCNC1 (ENSG00000129159), KCNA5 (ENSG00000130037), KCNC3 (ENSG00000131398), KCNA10 (ENSG00000143105), KCNA6 (ENSG00000151079), KCNS2 (ENSG00000156486), KCNB1 (ENSG00000158445), KCNF1 (ENSG00000162975), KCNV1 (ENSG00000164794), KCNC2 (ENSG00000166006), KCNV2 (ENSG00000168263), KCNG4 (ENSG00000168418), KCNS3 (ENSG00000170745), KCNG3 (ENSG00000171126), KCND3 (ENSG00000171385), KCNA3 (ENSG00000177272), KCNA2 (ENSG00000177301), KCNG2 (ENSG00000178342), KCNA4 (ENSG00000182255), KCNB2 (ENSG00000182674), KCNQ3 (ENSG00000184156), KCND2 (ENSG00000184408), KCNQ5 (ENSG00000185760)

Protein

Protein identifiers

Potassium voltage-gated channel subfamily KQT member 4 — P56696 (reviewed: P56696)

Alternative names: KQT-like 4, Potassium channel subunit alpha KvLQT4, Voltage-gated potassium channel subunit Kv7.4

All UniProt accessions (2): P56696, H0Y6N7

UniProt curated annotations — full annotation on UniProt →

Function. Pore-forming subunit of the voltage-gated potassium (Kv) channel involved in the regulation of sensory cells excitability in the cochlea. KCNQ4/Kv7.4 channel is composed of 4 pore-forming subunits assembled as tetramers. Promotes the outflow of potassium ions in the repolarization phase of action potential which plays a role in regulating membrane potential of excitable cells. The channel conducts a slowly activating and deactivating current. Current often shows some inward rectification at positive potentials. Channel may be selectively permeable in vitro to other cations besides potassium, in decreasing order of affinity K(+) = Rb(+) > Cs(+) > Na(+). Important for normal physiological function of inner ear such as sensory perception of sound.

Subunit / interactions. Homotetramer. Interacts (via C-terminus) with calmodulin; forms a heterooctameric structure (with 4:4 KCNQ1:CALM stoichiometry); the interaction is calcium-independent, constitutive, participates in the proper assembly of a functional channel. The interaction with calcium-free CALM controls channel trafficking whereas interaction with calcium-bound CALM regulates channel gating. May form a functional heteromultimeric channel with KCNQ3. Interacts with HSP90AB1; promotes cell surface expression of KCNQ4.

Subcellular location. Basal cell membrane.

Tissue specificity. Expressed in the outer, but not the inner, sensory hair cells of the cochlea. Slightly expressed in heart, brain and skeletal muscle.

Disease relevance. Deafness, autosomal dominant, 2A (DFNA2A) [MIM:600101] A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Two molecules of phosphatidylinositol-4,5-bisphosphate (PIP2-I and PIP2-II) are essential to activate KCNQ4 channel by inducing the coupling of the voltage-sensing domain (VSD) and the pore-forming domain (PD). Upon channel activation, PIP2-I and PIP2-II disrupt the VSD-calmodulin/CALM interaction, causing the release of CALM from the VSD which triggers the opening of the gate. Calcium suppresses KCNQ4 channel current through calcium-bound CALM C-terminus. Therefore CALM acts as calcium sensor that controls channel activity. ML213 potentiates KCNQ4 channel. KCNQ4 channel is blocked by linopirdin, XE991 and bepridil, whereas clofilium is without significant effect. Muscarinic agonist oxotremorine-M strongly suppress KCNQ4 current in CHO cells in which cloned KCNQ4 channels were coexpressed with M1 muscarinic receptors.

Domain organisation. Each channel subunit contains six transmembrane segments (S1-S6) with S1-S4 forming one voltage sensing domain (VSD) and S5-S6 contributing to form one quarter of an interlocking pore-forming domain (PD). The CALM binding domains correspond to the first two membrane-proximal helical regions that interact with a single calmodulin/CALM molecule forming a clamp-like structure. CALM N-terminus binds to the second helix in both calcium-free and calcium-bound forms and regulates channel trafficking. CALM C-terminus binds to the first helice in calcium-free form; this interaction is disrupted by calcium binding which regulates channel electrophysiological activity. The C-terminal assembly domain carries the major determinants of tetramerization and subunit assembly specificity. Its coiled-coil region is four-stranded.

Miscellaneous. Mutagenesis experiments were carried out by expressing in Xenopus oocytes KCNQ4 mutants either individually (homomultimers) or in combination with wild-type KCNQ4 (mut/wt homomultimers) in a ratio of 1:1, to mimic the situation in a heterozygous DFNA2 patient.

Similarity. Belongs to the potassium channel family. KQT (TC 1.A.1.15) subfamily. Kv7.4/KCNQ4 sub-subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P56696-1	1	yes
P56696-2	2

RefSeq proteins (2): NP_004691, NP_751895 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003937	K_chnl_volt-dep_KCNQ	Family
IPR005821	Ion_trans_dom	Domain
IPR013821	K_chnl_volt-dep_KCNQ_C	Domain

Pfam: PF00520, PF03520

Catalyzed reactions (Rhea), 1 shown:

• K(+)(in) = K(+)(out) (RHEA:29463)

UniProt features (106 total): mutagenesis site 33, helix 19, binding site 9, topological domain 8, sequence variant 8, region of interest 7, transmembrane region 6, turn 6, compositionally biased region 3, strand 3, chain 1, intramembrane region 1, coiled-coil region 1, splice variant 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
2OVC	X-RAY DIFFRACTION	2.07
6N5W	X-RAY DIFFRACTION	2.15
6B8P	X-RAY DIFFRACTION	2.2
6B8N	X-RAY DIFFRACTION	2.2
6B8L	X-RAY DIFFRACTION	2.3
6B8M	X-RAY DIFFRACTION	2.3
7BYL	ELECTRON MICROSCOPY	2.5
4GOW	X-RAY DIFFRACTION	2.6
7VNP	ELECTRON MICROSCOPY	2.79
7VNR	ELECTRON MICROSCOPY	2.8
7VNQ	ELECTRON MICROSCOPY	2.96
7BYM	ELECTRON MICROSCOPY	3.1
7BYN	ELECTRON MICROSCOPY	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P56696-F1	66.37	0.24

Functional residue map

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

Ligand- & substrate-binding residues (9): 93; 172; 219; 220; 220 (in chain a); 225; 235 (in chain b); 330 (in chain a); 333 (in chain a)

Mutagenesis-validated functional residues (33):

Position	Phenotype
93	shifted activation curve of kcnq4 toward positive potentials compared to wild-type. no difference in current density.
95	shifted activation curve of kcnq4 toward positive potentials compared to wild-type. no difference in current density.
123	no effect on inhibition by potassium channel toxin sstx.
124	no effect on inhibition by potassium channel toxin sstx.
125	no effect on inhibition by potassium channel toxin sstx.
126	no effect on inhibition by potassium channel toxin sstx.
194	no effect on inhibition by potassium channel toxin sstx.
196	no effect on inhibition by potassium channel toxin sstx.
205	no effect on inhibition by potassium channel toxin sstx.
210	no effect on inhibition by potassium channel toxin sstx.
213	no effect on inhibition by potassium channel toxin sstx.
216	no effect on inhibition by potassium channel toxin sstx.
220	shifted activation curve of kcnq4 toward positive potentials compared to wild-type. no difference in current density.
225	shifted activation curve of kcnq4 toward positive potentials compared to wild-type. no difference in current density.
236	loss of detectable current.
261	no effect on inhibition by potassium channel toxin sstx.
262	no effect on inhibition by potassium channel toxin sstx.
266	resistant to inhibition by potassium channel toxin sstx. normal voltage activation.
268	no effect on inhibition by potassium channel toxin sstx.
272	no effect on inhibition by potassium channel toxin sstx.
288	resistant to inhibition by potassium channel toxin sstx. normal voltage activation.
290	no effect on inhibition by potassium channel toxin sstx.
292	no effect on inhibition by potassium channel toxin sstx.
295	no effect on inhibition by potassium channel toxin sstx.
298	no effect on inhibition by potassium channel toxin sstx.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-1296072	Voltage gated Potassium channels
R-HSA-9662360	Sensory processing of sound by inner hair cells of the cochlea
R-HSA-9662361	Sensory processing of sound by outer hair cells of the cochlea
R-HSA-112316	Neuronal System
R-HSA-1296071	Potassium Channels
R-HSA-9659379	Sensory processing of sound
R-HSA-9709957	Sensory Perception

MSigDB gene sets: 160 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, RRAGTTGT_UNKNOWN, MYOGENIN_Q6, REACTOME_VOLTAGE_GATED_POTASSIUM_CHANNELS, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, REACTOME_POTASSIUM_CHANNELS, LFA1_Q6, MAZ_Q6, AP4_Q6, CAGCTG_AP4_Q5, GOBP_MONOATOMIC_CATION_TRANSPORT, CATRRAGC_UNKNOWN, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_EAR_DEVELOPMENT, GOBP_EMBRYONIC_ORGAN_MORPHOGENESIS

GO Biological Process (7): potassium ion transport (GO:0006813), sensory perception of sound (GO:0007605), inner ear morphogenesis (GO:0042472), potassium ion transmembrane transport (GO:0071805), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085)

GO Molecular Function (4): voltage-gated potassium channel activity (GO:0005249), potassium channel activity (GO:0005267), monoatomic ion channel activity (GO:0005216), protein binding (GO:0005515)

GO Cellular Component (5): plasma membrane (GO:0005886), voltage-gated potassium channel complex (GO:0008076), basal plasma membrane (GO:0009925), membrane (GO:0016020), monoatomic ion channel complex (GO:0034702)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Sensory processing of sound	2
Potassium Channels	1
Neuronal System	1
Sensory Perception	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	2
metal ion transport	1
sensory perception of mechanical stimulus	1
ear morphogenesis	1
embryonic morphogenesis	1
inner ear development	1
potassium ion transport	1
monoatomic cation transmembrane transport	1
monoatomic ion transport	1
transmembrane transport	1
cellular process	1
potassium channel activity	1
voltage-gated monoatomic cation channel activity	1
monoatomic cation channel activity	1
potassium ion transmembrane transporter activity	1
monoatomic ion transmembrane transporter activity	1
channel activity	1
binding	1
membrane	1
cell periphery	1
potassium channel complex	1
plasma membrane protein complex	1
basal part of cell	1
plasma membrane region	1
cellular anatomical structure	1
transmembrane transporter complex	1

Protein interactions and networks

STRING

1940 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCNQ4	KCNE4	Q8WWG9	966
KCNQ4	GJB3	O75712	931
KCNQ4	KCNE1	P15382	880
KCNQ4	KCNE3	Q9Y6H6	836
KCNQ4	KCNQ5	Q9NR82	761
KCNQ4	KCNH2	Q12809	737
KCNQ4	PCDH15	Q96QU1	717
KCNQ4	TMC1	Q8TDI8	701
KCNQ4	SLC26A5	P58743	696
KCNQ4	GJB2	P29033	674
KCNQ4	CDH23	Q9H251	668
KCNQ4	OTOF	Q9HC10	663
KCNQ4	EYA4	O95677	646
KCNQ4	MYO6	Q9UM54	645
KCNQ4	SLC26A4	O43511	639

IntAct

2 interactions, top by confidence:

A	B	Type	Score
M		psi-mi:“MI:0914”(association)	0.350

BioGRID (50): KCNQ4 (Negative Genetic), KCNQ4 (Negative Genetic), NT5M (Negative Genetic), KCNQ4 (Negative Genetic), KCNQ4 (Positive Genetic), KCNQ4 (Positive Genetic), KCNQ4 (Affinity Capture-MS), KCNQ4 (Affinity Capture-Western), Hap1 (Affinity Capture-Western), Hap1 (Reconstituted Complex), Calm2 (Two-hybrid), Hap1 (Two-hybrid), Mmp14 (Two-hybrid), Phf20l1 (Two-hybrid), Sptbn1 (Two-hybrid)

ESM2 similar proteins: A0A2R8VHF7, A0JM23, A2QRA0, A4IIA7, A4IIV4, A6NFN9, A6NHR9, A7MBF6, F4IG73, F4JSE7, O17482, O95876, P12540, P21784, P34089, P38899, P55895, P56696, Q08AW4, Q0D2D7, Q12789, Q13829, Q28DC9, Q2WGJ8, Q3E7Y5, Q3UUE9, Q4R907, Q4VXA5, Q5BK83, Q5EA90, Q5F476, Q5HZS2, Q5M9F0, Q5RAX4, Q5RBH4, Q5RD21, Q6AYL6, Q6DGA7, Q6PIY5, Q70XZ2

Diamond homologs: A4K2M4, A4K2P6, A4K2T1, A4K2Y2, A6H8H5, B2RQA1, G5EFC3, O18868, O35174, O43526, O88759, O88943, O97531, P08510, P10499, P15384, P15385, P15387, P15388, P16388, P16389, P16390, P17658, P17659, P17970, P17971, P17972, P19024, P22001, P22459, P22460, P22462, P22739, P25122, P48547, P50638, P56696, P59994, P59995, P63141

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
KCNQ4	“up-regulates quantity”	potassium(1+)	relocalization

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	24
Likely pathogenic	25
Uncertain significance	254
Likely benign	123
Benign	53

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
156337	NM_004700.4(KCNQ4):c.859G>C (p.Gly287Arg)	Pathogenic
179111	NM_004700.4(KCNQ4):c.459del (p.Ala154fs)	Pathogenic
208364	NM_004700.4(KCNQ4):c.228_229dup (p.His77fs)	Pathogenic
208365	NM_004700.4(KCNQ4):c.689T>A (p.Val230Glu)	Pathogenic
208366	NM_004700.4(KCNQ4):c.803CCT[1] (p.Ser269del)	Pathogenic
208367	NM_004700.4(KCNQ4):c.808T>C (p.Tyr270His)	Pathogenic
208368	NM_004700.4(KCNQ4):c.823T>C (p.Trp275Arg)	Pathogenic
208369	NM_004700.4(KCNQ4):c.871C>T (p.Pro291Ser)	Pathogenic
208372	NM_004700.4(KCNQ4):c.1044_1051del (p.Ala349Profs)	Pathogenic
2978740	NM_004700.4(KCNQ4):c.480C>G (p.Tyr160Ter)	Pathogenic
2993508	NM_004700.4(KCNQ4):c.44_60dup (p.Ala21fs)	Pathogenic
3287740	NM_004700.4(KCNQ4):c.1630del (p.Val544fs)	Pathogenic
4764224	NM_004700.4(KCNQ4):c.777_778delinsCT (p.Glu260Ter)	Pathogenic
4769745	NM_004700.4(KCNQ4):c.1277del (p.Phe426fs)	Pathogenic
6241	NM_004700.4(KCNQ4):c.853G>A (p.Gly285Ser)	Pathogenic
6242	NM_004700.4(KCNQ4):c.827G>C (p.Trp276Ser)	Pathogenic
6244	NM_004700.4(KCNQ4):c.853G>T (p.Gly285Cys)	Pathogenic
6245	NM_004700.4(KCNQ4):c.212_224del (p.Gln71fs)	Pathogenic
6246	NM_004700.4(KCNQ4):c.842T>C (p.Leu281Ser)	Pathogenic
6247	NM_004700.4(KCNQ4):c.821T>A (p.Leu274His)	Pathogenic
6248	NM_004700.4(KCNQ4):c.211del (p.Gln71fs)	Pathogenic
6249	NM_004700.4(KCNQ4):c.886G>A (p.Gly296Ser)	Pathogenic
625441	NM_004700.4(KCNQ4):c.261_269del (p.Tyr88_Val90del)	Pathogenic
65893	NM_004700.4(KCNQ4):c.725G>A (p.Trp242Ter)	Pathogenic
1064936	NM_004700.4(KCNQ4):c.1251del (p.Cys418fs)	Likely pathogenic
1184480	NM_004700.4(KCNQ4):c.857A>C (p.Tyr286Ser)	Likely pathogenic
1699203	NM_004700.4(KCNQ4):c.826T>C (p.Trp276Arg)	Likely pathogenic
1806181	NM_004700.4(KCNQ4):c.670T>C (p.Trp224Arg)	Likely pathogenic
2120280	NM_004700.4(KCNQ4):c.406-2A>G	Likely pathogenic
2135429	NM_004700.4(KCNQ4):c.886G>T (p.Gly296Cys)	Likely pathogenic

SpliceAI

3106 predictions. Top by Δscore:

Variant	Effect	Δscore
1:40784406:ATG:A	donor_loss	1.0000
1:40784407:TGT:T	donor_loss	1.0000
1:40784408:G:GG	donor_gain	1.0000
1:40784409:TGAG:T	donor_loss	1.0000
1:40817257:A:AG	acceptor_gain	1.0000
1:40817258:A:G	acceptor_gain	1.0000
1:40817262:CA:C	acceptor_loss	1.0000
1:40817263:A:AC	acceptor_loss	1.0000
1:40817263:A:AG	acceptor_gain	1.0000
1:40817264:G:GT	acceptor_gain	1.0000
1:40817264:GA:G	acceptor_gain	1.0000
1:40817264:GAT:G	acceptor_gain	1.0000
1:40817264:GATT:G	acceptor_gain	1.0000
1:40817264:GATTT:G	acceptor_gain	1.0000
1:40817351:TCTTG:T	donor_gain	1.0000
1:40817352:CTTG:C	donor_gain	1.0000
1:40817353:TTG:T	donor_gain	1.0000
1:40817354:TG:T	donor_gain	1.0000
1:40817355:GG:G	donor_gain	1.0000
1:40817355:GGTA:G	donor_loss	1.0000
1:40817356:G:GA	donor_loss	1.0000
1:40817356:G:GG	donor_gain	1.0000
1:40817357:T:A	donor_loss	1.0000
1:40818503:A:AG	acceptor_gain	1.0000
1:40818504:G:GG	acceptor_gain	1.0000
1:40818644:G:GT	donor_gain	1.0000
1:40818676:GCAAG:G	donor_gain	1.0000
1:40818678:AAGGT:A	donor_loss	1.0000
1:40818679:AGG:A	donor_loss	1.0000
1:40818681:G:GG	donor_gain	1.0000

AlphaMissense

4486 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:40818185:T:C	F143L	1.000
1:40818187:C:A	F143L	1.000
1:40818187:C:G	F143L	1.000
1:40818263:T:C	F169L	1.000
1:40818264:T:C	F169S	1.000
1:40818264:T:G	F169C	1.000
1:40818265:T:A	F169L	1.000
1:40818265:T:G	F169L	1.000
1:40818505:A:T	D178V	1.000
1:40818585:A:C	S205R	1.000
1:40818587:C:A	S205R	1.000
1:40818587:C:G	S205R	1.000
1:40818594:T:C	F208L	1.000
1:40818596:C:A	F208L	1.000
1:40818596:C:G	F208L	1.000
1:40818613:T:G	M214R	1.000
1:40818642:T:A	W224R	1.000
1:40818642:T:C	W224R	1.000
1:40818649:T:C	L226P	1.000
1:40819351:T:C	L238P	1.000
1:40819362:T:A	W242R	1.000
1:40819362:T:C	W242R	1.000
1:40819371:G:A	G245R	1.000
1:40819371:G:C	G245R	1.000
1:40819371:G:T	G245W	1.000
1:40819372:G:A	G245E	1.000
1:40819464:T:A	W276R	1.000
1:40819464:T:C	W276R	1.000
1:40819467:G:A	G277R	1.000
1:40819467:G:C	G277R	1.000

dbSNP variants (sampled 300 via entrez): RS1000095328 (1:40795745 G>A), RS1000135419 (1:40783756 C>G,T), RS1000156551 (1:40804474 A>G), RS1000173085 (1:40823851 C>T), RS1000206656 (1:40823048 T>C), RS1000209046 (1:40805911 G>A), RS1000345316 (1:40807490 C>A,T), RS1000403692 (1:40804131 C>T), RS1000410241 (1:40835541 T>C), RS1000560137 (1:40785935 G>A), RS1000572547 (1:40827232 G>C), RS1000592591 (1:40819662 T>C), RS1000678342 (1:40821779 T>C), RS1000705787 (1:40819389 T>C), RS1000765527 (1:40815132 C>T)

Disease associations

OMIM: gene MIM:603537 | disease phenotypes: MIM:600101, MIM:124900

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal dominant nonsyndromic hearing loss 2A	Definitive	Autosomal dominant
nonsyndromic genetic hearing loss	Definitive	Autosomal dominant
autosomal dominant nonsyndromic hearing loss	Supportive	Autosomal dominant
hearing loss disorder	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Definitive	AD

Mondo (4): autosomal dominant nonsyndromic hearing loss 2A (MONDO:0010817), hearing loss disorder (MONDO:0005365), nonsyndromic genetic hearing loss (MONDO:0019497), autosomal dominant nonsyndromic hearing loss (MONDO:0019587)

Orphanet (3): Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635), Rare genetic deafness (Orphanet:96210), Rare non-syndromic genetic deafness (Orphanet:87884)

HPO phenotypes

4 total (4 of 4 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000360	Tinnitus
HP:0000365	Hearing impairment
HP:0003676	Progressive

GWAS associations

72 associations (top):

Study	Trait	p-value
GCST010796_3901	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-21
GCST010796_3902	Electrocardiogram morphology (amplitude at temporal datapoints)	8.000000e-21
GCST010796_3903	Electrocardiogram morphology (amplitude at temporal datapoints)	9.000000e-20
GCST010796_3904	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-19
GCST010796_3905	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-18
GCST010796_3906	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-16
GCST010796_3907	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-15
GCST010796_3908	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-14
GCST010796_3909	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-13
GCST010796_3910	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-12
GCST010796_3911	Electrocardiogram morphology (amplitude at temporal datapoints)	9.000000e-11
GCST010796_3912	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-09
GCST010796_3913	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-08
GCST010796_3914	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-26
GCST010796_3915	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-26
GCST010796_3944	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-10
GCST010796_3945	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-11
GCST010796_3946	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-08
GCST010796_3947	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_3948	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-10
GCST010796_3949	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-10
GCST010796_3950	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-10
GCST010796_4476	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-21
GCST010796_4477	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-22
GCST010796_4478	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-21
GCST010796_4479	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-20
GCST010796_4480	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-21
GCST010796_4481	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-10
GCST010796_4482	Electrocardiogram morphology (amplitude at temporal datapoints)	7.000000e-11
GCST010796_4483	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004327	electrocardiography

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
C567441	Deafness, Autosomal Dominant 2A (supp.)
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (5): CHEMBL2362996 (PROTEIN FAMILY), CHEMBL2363063 (PROTEIN FAMILY), CHEMBL3576 (SINGLE PROTEIN), CHEMBL3707192 (PROTEIN COMPLEX), CHEMBL4523611 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 4,070 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL41355	EZOGABINE	4	3,996
CHEMBL266510	FLINDOKALNER	3	74

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: vgic — Voltage-gated potassium channels (K_v)

Most potent curated ligand interactions (13 total), top 13:

Ligand	Action	Affinity	Parameter
ML252	Inhibitor	6.7	pIC50
ML213	Activation	6.3	pEC50
retigabine derivative 10g	Activator	6.0	pEC50
XE991	Inhibitor	5.3	pIC50
retigabine	Activator	5.2	pEC50
flindokalner	Activator	5.0	pEC50
bepridil	Channel blocker	5.0	pIC50
zinc pyrithione	Activator	5.0	pEC50
(S)-N-[1-(3-morpholin-4-yl-phenyl)-ethyl]-3-phenyl-acrylamide	Activator	5.0	pIC50
NC00075159	Activation	5.0	pEC50
linopirdine	Inhibitor	4.9	pIC50
PIP2	Activator	3.7	pEC50
tetraethylammonium	Channel blocker	1.3	pIC50

ChEMBL bioactivities

23 potent at pChembl≥5 of 23 total, top 23 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.82	Ki	0.15	nM	CHEMBL5722941
9.74	IC50	0.18	nM	CHEMBL5722941
7.70	EC50	20	nM	CHEMBL4277250
7.10	EC50	80	nM	CHEMBL4457044
7.06	EC50	87	nM	CHEMBL5185685
7.00	EC50	100	nM	CHEMBL4287894
7.00	EC50	100	nM	CHEMBL4545892
6.80	EC50	160	nM	CHEMBL4288707
6.70	IC50	200	nM	CHEMBL2164048
6.50	EC50	320	nM	CHEMBL5200636
6.20	EC50	625	nM	CHEMBL3621437
6.18	EC50	660	nM	CHEMBL4549229
6.11	EC50	780	nM	CHEMBL4588394
6.05	EC50	890	nM	CHEMBL4448132
6.04	EC50	910	nM	CHEMBL4458793
5.85	EC50	1420	nM	CHEMBL4438770
5.80	EC50	1600	nM	CHEMBL1703636
5.70	EC50	1980	nM	EZOGABINE
5.69	EC50	2030	nM	CHEMBL4450214
5.62	EC50	2400	nM	FLINDOKALNER
5.40	EC50	4000	nM	CHEMBL4287478
5.23	EC50	5900	nM	EZOGABINE
5.19	EC50	6400	nM	CHEMBL5178988

PubChem BioAssay actives

23 with measured affinity, of 158 total; 21 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
3-[(1R,2aS,4S,5aS,8aS,10S,11aR,14aS,16S,17aS,19S,20aS,22S,23aS,25S,26aS,28S,29aS,31R,32aS,35aS,36R,38aS,39S,41aS,42S,44aS,45S,48R,50aS,51S,53aS,54S,56aS,57S,59aS,60S,63S,66S,69S,72S,75S,78S,87R,93S,96S,99S)-17a,20a,23a,53a,63-pentakis(4-aminobutyl)-31-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-5-carbamimidamido-2-[[(2S)-5-carbamimidamido-2-[[(2S)-1-[(2S)-5-oxopyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]amino]pentanoyl]amino]pentanoyl]amino]hexanoyl]amino]-4-methylpentanoyl]amino]-16,29a,72,78-tetrakis(2-amino-2-oxoethyl)-14a,26a-bis(3-amino-3-oxopropyl)-2a,38a,66-tribenzyl-28,50a,57-tris[(2S)-butan-2-yl]-4,5a,19,42,45,69-hexakis(3-carbamimidamidopropyl)-51,54-bis(2-carboxyethyl)-56a,99-bis(carboxymethyl)-36-[[(2S,3S)-1-(carboxymethylamino)-3-methyl-1-oxopentan-2-yl]carbamoyl]-39,60-bis[(1R)-1-hydroxyethyl]-75,93-bis(hydroxymethyl)-32a,35a,59a-tris[(4-hydroxyphenyl)methyl]-22-(1H-imidazol-4-ylmethyl)-96-(1H-indol-3-ylmethyl)-41a-methyl-25-(2-methylpropyl)-1a,3,4a,6,7a,9,10a,13a,15,16a,18,19a,21,22a,24,25a,27,28a,30,31a,34a,37a,38,40a,41,43a,44,47,49a,50,52a,53,55a,56,58a,59,61a,62,65,68,71,74,77,80,83,86,89,92,95,98-pentacontaoxo-33,34,63a,64a,67a,68a-hexathia-a,2,3a,5,6a,8,9a,12a,14,15a,17,18a,20,21a,23,24a,26,27a,29,30a,33a,36a,37,39a,40,42a,43,46,48a,49,51a,52,54a,55,57a,58,60a,61,64,67,70,73,76,79,82,85,88,91,94,97-pentacontazapentacyclo[85.74.4.448,111.010,14.0144,148]nonahexacontahectan-8a-yl]propanoic acid	2198828: Binding affinity to KV channel (unknown origin) assessed as inhibition constant	ki	0.0001	uM
trans-(1S,2S)-5,5-difluoro-N-[(1R)-2-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl]-2-phenylcyclohexane-1-carboxamide	1414249: Activation of human Kv7.4 by patch clamp method	ec50	0.0200	uM
3,3-dimethyl-N-[1-[[4-(trifluoromethyl)phenyl]methyl]indol-5-yl]butanamide	1604642: Activation of human Kv7.4 expressed in CHO cells assessed as increase in channel current amplitude by whole cell patch clamp electrophysiology assay	ec50	0.0800	uM
ethyl N-[2-amino-3,5-difluoro-4-[[4-(trifluoromethyl)phenyl]methylamino]phenyl]carbamate	1861513: Agonist activity at Kv7.4 (unknown origin) expressed in CHO cells co-expressing GFP	ec50	0.0870	uM
trans-(1S,2S)-N-[(1R)-1-(3-chlorophenyl)-2-hydroxyethyl]-5,5-difluoro-2-phenylcyclohexane-1-carboxamide	1414249: Activation of human Kv7.4 by patch clamp method	ec50	0.1000	uM
N-[1-[[4-(trifluoromethyl)phenyl]methyl]indol-5-yl]heptanamide	1604642: Activation of human Kv7.4 expressed in CHO cells assessed as increase in channel current amplitude by whole cell patch clamp electrophysiology assay	ec50	0.1000	uM
4,5-difluoro-N-[(1S)-1-(3-methylsulfonylphenyl)ethyl]-2-phenoxybenzamide	1414249: Activation of human Kv7.4 by patch clamp method	ec50	0.1600	uM
(2S)-2-phenyl-N-(2-pyrrolidin-1-ylphenyl)butanamide	697778: Antagonist activity at KCNQ4 expressed in CHO cells incubated for 3 mins by automated patch clamp assay	ic50	0.2000	uM
cyclopropyl N-[2-amino-3,5,6-trifluoro-4-[[3-fluoro-5-(trifluoromethyl)-2-pyridinyl]methylamino]phenyl]carbamate	1861513: Agonist activity at Kv7.4 (unknown origin) expressed in CHO cells co-expressing GFP	ec50	0.3200	uM
N-[4,6-dimethoxy-2-(4-methoxypiperidin-1-yl)pyrimidin-5-yl]-3,3-dimethylbutanamide	1249422: Activation of human Kv7.4 expressed in CHOK1 cells	ec50	0.6250	uM
ethyl N-[2-amino-3-fluoro-4-[[6-(trifluoromethyl)-3-pyridinyl]methylamino]phenyl]carbamate	1861513: Agonist activity at Kv7.4 (unknown origin) expressed in CHO cells co-expressing GFP	ec50	0.6600	uM
tert-butyl N-[2-(ethoxycarbonylamino)-5-[(4-fluorophenyl)methyl-prop-2-ynylamino]phenyl]carbamate	1586934: Agonist activity at human KCNQ4 expressed in CHOK1 cells by whole cell patch clamp assay	ec50	0.7800	uM
ethyl N-[2-(ethoxycarbonylamino)-4-[(4-fluorophenyl)methyl-prop-2-ynylamino]phenyl]carbamate	1586924: Activation of human homomeric KCNQ4 expressed in CHOK1 cells at -10 mV by whole cell patch clamp assay	ec50	0.8900	uM
cyclopropyl N-[2-amino-3-fluoro-4-[[4-(trifluoromethyl)phenyl]methylamino]phenyl]carbamate	1861513: Agonist activity at Kv7.4 (unknown origin) expressed in CHO cells co-expressing GFP	ec50	0.9100	uM
tert-butyl N-[2-(ethoxycarbonylamino)-4-[(4-fluorophenyl)methyl-prop-2-ynylamino]phenyl]carbamate	1586934: Agonist activity at human KCNQ4 expressed in CHOK1 cells by whole cell patch clamp assay	ec50	1.4200	uM
N-(2,4,6-trimethylphenyl)bicyclo[2.2.1]heptane-2-carboxamide	1414249: Activation of human Kv7.4 by patch clamp method	ec50	1.6000	uM
ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]carbamate	1604642: Activation of human Kv7.4 expressed in CHO cells assessed as increase in channel current amplitude by whole cell patch clamp electrophysiology assay	ec50	1.9800	uM
tert-butyl N-[4-[(4-fluorophenyl)methyl-prop-2-ynylamino]-2-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]carbamate	1586934: Agonist activity at human KCNQ4 expressed in CHOK1 cells by whole cell patch clamp assay	ec50	2.0300	uM
(3S)-3-(5-chloro-2-methoxyphenyl)-3-fluoro-6-(trifluoromethyl)-1H-indol-2-one	726088: Positive modulatory activity at voltage-gated K channel 7.4 (unknown origin)	ec50	2.4000	uM
trans-(1S,2S)-5,5-difluoro-2-phenyl-N-[(1S)-1-phenylethyl]cyclohexane-1-carboxamide	1414249: Activation of human Kv7.4 by patch clamp method	ec50	4.0000	uM
N-(2,4-dibromophenyl)-2-[[4-methyl-5-[(4-methylphenyl)methylsulfanylmethyl]-1,2,4-triazol-3-yl]sulfanyl]acetamide	1870622: Agonist activity at human KCNQ4 channel expressed in CHO cells assessed as increase in outward current by patch clamp electrophysiology method	ec50	6.4000	uM

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
ezogabine	increases activity, increases export, increases import	2
Benzo(a)pyrene	affects methylation	2
Thallium	increases activity, increases import	2
Valproic Acid	increases expression, increases methylation	2
aristolochic acid I	increases expression	1
trichostatin A	increases expression	1
aflatoxin B2	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1
N-(1-(3-morpholin-4-ylphenyl)ethyl)-3-phenylacrylamide	increases activity	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	increases expression	1
Amphotericin B	decreases expression	1
Arsenic	affects methylation	1
Cisplatin	decreases expression	1
Cyclophosphamide	decreases expression	1
Estradiol	increases expression	1
Gentamicins	decreases expression	1
Lipopolysaccharides	decreases reaction, increases expression	1
Rotenone	increases expression	1
Rubidium	increases activity, increases export	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1
Vanadium	decreases expression	1
Aflatoxin B1	decreases methylation	1
Acrylamide	increases activity	1
Quinazolinones	increases activity, increases import	1
Coal Ash	decreases expression	1

ChEMBL screening assays

48 unique, capped per target: 42 binding, 3 functional, 2 admet, 1 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1787442	Binding	Inhibition of human recombinant Kv channel at 10 uM by radioligand binding assay	Structure-activity relationships of pyrrole based S-nitrosoglutathione reductase inhibitors: pyrrole regioisomers and propionic acid replacement. — Bioorg Med Chem Lett
CHEMBL5522525	Toxicity	Inhibition of human K+ channel by automated electrophysiology	Discovery of Clinical Candidate AZD5462, a Selective Oral Allosteric RXFP1 Agonist for Treatment of Heart Failure. — J Med Chem
CHEMBL1794543	Functional	PUBCHEM_BIOASSAY: Mode of action assay-Dose response assay for the identification of selective activators of KCNQ2 potassium channels in the KCNQ4 expressing cells on automated patch clamp. (Class of assay: confirmatory) [Related pubchem as	PubChem BioAssay data set

Cellosaurus cell lines

2 cell lines: 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1KC	PrecisION hKv7.4-HEK	Transformed cell line	Female
CVCL_D1KD	PrecisION hKv7.4/Kv7.5-HEK	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT00486577	PHASE2/PHASE3	COMPLETED	Chronic Electrical Stimulation of the Auditory Cortex for Intractable Tinnitus
NCT00789061	PHASE2/PHASE3	UNKNOWN	Applying Proton Pump Inhibitor to Prevent and Treat Acute Fluctuating Hearing Loss in Patients With SLC26A4 Mutation
NCT01423409	PHASE2/PHASE3	COMPLETED	Multicenter Trial Assessing an Innovative VAS of Pain Among Deaf People
NCT05786378	PHASE2/PHASE3	UNKNOWN	Assessment of The Efficacy of Intratympanic Platelet Rich Plasma for Treatment of Sensorineural Hearing Loss.
NCT01108601	PHASE1/PHASE2	UNKNOWN	Transtympanic Ringer’s Lactate for the Prevention of Cisplatin Ototoxicity
NCT01621256	PHASE1/PHASE2	COMPLETED	Efficacy, Safety, and Tolerability of Ancrod in Patients With Sudden Hearing Loss
NCT06370351	PHASE1/PHASE2	RECRUITING	A Phase I/II Clinical Trial with SENS-501 in Children Suffering from Severe to Profound Hearing Loss Due to Otoferlin (OTOF) Mutations
NCT06545175	PHASE1/PHASE2	RECRUITING	Intracochlear Application of VSF1.01 for the Reduction of Cochlear Implant Surgery Related Trauma
NCT07304024	PHASE1/PHASE2	RECRUITING	A Treatment for a Form of Age-Related Central Auditory Processing Disorder Consisting of Clemastine Fumarate Plus Engineered Sound
NCT01109576	EARLY_PHASE1	COMPLETED	Workshops for Veterans With Vision and Hearing Loss