KCND3

Summary

KCND3 (potassium voltage-gated channel subfamily D member 3, HGNC:6239) is a protein-coding gene on chromosome 1p13.2, encoding A-type voltage-gated potassium channel KCND3 (Q9UK17). Pore-forming (alpha) subunit of voltage-gated A-type potassium channels that mediates transmembrane potassium transport in excitable membranes, in brain and heart.

Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shal-related subfamily, members of which form voltage-activated A-type potassium ion channels and are prominent in the repolarization phase of the action potential. This member includes two isoforms with different sizes, which are encoded by alternatively spliced transcript variants of this gene.

Source: NCBI Gene 3752 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spinocerebellar ataxia type 19/22 (Strong, GenCC) — +3 more curated relationships
• GWAS associations: 287
• Clinical variants (ClinVar): 725 total — 11 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 49
• Druggable target: yes — 10 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001378969

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6239
Approved symbol	KCND3
Name	potassium voltage-gated channel subfamily D member 3
Location	1p13.2
Locus type	gene with protein product
Status	Approved
Aliases	Kv4.3, KSHIVB
Ensembl gene	ENSG00000171385
Ensembl biotype	protein_coding
OMIM	605411
Entrez	3752

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 6 protein_coding, 3 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000302127, ENST00000315987, ENST00000369697, ENST00000703640, ENST00000703641, ENST00000703642, ENST00000703643, ENST00000896065, ENST00000896066, ENST00000896067

RefSeq mRNA: 4 — MANE Select: NM_001378969 NM_001378969, NM_001378970, NM_004980, NM_172198

CCDS: CCDS843, CCDS844

Canonical transcript exons

ENST00000302127 — 8 exons

Exon	Start	End
ENSE00001159838	111777026	111777273
ENSE00001159844	111778436	111778492
ENSE00001159851	111780225	111780314
ENSE00001159860	111780690	111780791
ENSE00001274673	111786944	111787106
ENSE00001325164	111770662	111776278
ENSE00001381593	111981621	111982798
ENSE00003908396	111989505	111989668

Expression profiles

Bgee: expression breadth ubiquitous, 262 present calls, max score 98.17.

FANTOM5 (CAGE): breadth broad, TPM avg 1.7228 / max 90.5013, expressed in 428 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
13847	0.8287	335
13845	0.5523	200
13846	0.2942	148
13844	0.0477	25

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar vermis	UBERON:0004720	98.17	gold quality
substantia nigra pars reticulata	UBERON:0001966	97.75	gold quality
lateral nuclear group of thalamus	UBERON:0002736	96.02	gold quality
substantia nigra pars compacta	UBERON:0001965	95.52	gold quality
paraflocculus	UBERON:0005351	94.94	gold quality
Brodmann (1909) area 23	UBERON:0013554	94.57	gold quality
middle temporal gyrus	UBERON:0002771	94.41	gold quality
cauda epididymis	UBERON:0004360	93.63	gold quality
parietal lobe	UBERON:0001872	92.96	gold quality
caput epididymis	UBERON:0004358	92.88	gold quality
postcentral gyrus	UBERON:0002581	92.84	gold quality
entorhinal cortex	UBERON:0002728	92.54	gold quality
corpus epididymis	UBERON:0004359	92.49	gold quality
superior frontal gyrus	UBERON:0002661	92.09	gold quality
primary visual cortex	UBERON:0002436	91.28	gold quality
lateral globus pallidus	UBERON:0002476	91.20	gold quality
Brodmann (1909) area 10	UBERON:0013541	91.20	gold quality
occipital lobe	UBERON:0002021	90.98	gold quality
frontal pole	UBERON:0002795	90.80	gold quality
cerebellum	UBERON:0002037	90.64	gold quality
CA1 field of hippocampus	UBERON:0003881	90.59	gold quality
Brodmann (1909) area 46	UBERON:0006483	90.58	gold quality
orbitofrontal cortex	UBERON:0004167	90.54	gold quality
ventral tegmental area	UBERON:0002691	90.37	gold quality
saphenous vein	UBERON:0007318	89.92	gold quality
dorsal root ganglion	UBERON:0000044	89.88	gold quality
cerebellar cortex	UBERON:0002129	89.82	gold quality
cerebellar hemisphere	UBERON:0002245	89.62	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.85	gold quality
endothelial cell	CL:0000115	88.61	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-114	yes	11.47
E-HCAD-25	yes	8.23
E-ANND-3	yes	5.41

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): REST, THRA, THRB

miRNA regulators (miRDB)

33 targeting KCND3, 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-4673	100.00	66.64	1490
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
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-4514	99.99	67.10	1870
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-148A-3P	99.74	73.77	1700
HSA-MIR-148B-3P	99.74	73.75	1700
HSA-MIR-152-3P	99.74	73.75	1703
HSA-MIR-1296-3P	99.72	64.04	636
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6715B-5P	99.64	69.63	1420
HSA-MIR-4269	99.55	69.89	1373
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-3922-3P	99.25	64.96	1136
HSA-MIR-3176	99.25	64.35	954
HSA-MIR-491-5P	99.13	65.98	1468
HSA-MIR-3127-3P	98.94	67.34	1055
HSA-MIR-6756-3P	98.94	66.79	1104
HSA-MIR-3190-5P	98.87	64.89	1345
HSA-MIR-1910-3P	98.44	67.51	1695
HSA-MIR-6511A-5P	98.13	67.47	1770

Literature-anchored findings (GeneRIF, showing 40)

• Kv4.3 promiscuously assembles with ancillary subunits in vitro, functionally modifying the encoded currents. (PMID:12297301)
• maps to chromosome 1p21-q21 and identification in Dutch autosomal dominant cerebellar ataxia family (PMID:12384780)
• Analysis with chimeric proteins between KChIP2 and NCS-1 reveals that the three regions of KChIP2 are necessary and sufficient for its effective binding to Kv4.3 protein (PMID:12928444)
• the two arginines in the cytosolic C-terminal domain of alpha-subunits of Kv4 subfamily strongly regulate the voltage dependence of channel activation, inactivation, and recovery (PMID:14645239)
• Both Kv4.3 and KChIP2 may contribute to epicardial-endocardial gradients in the transient outward current in normal and failing hearts. (PMID:15498806)
• mutations in KCND2 and KCND3 are not a frequent cause of long QT syndrome (PMID:15563876)
• Co-expression of SGK1, but not of SGK2 or SGK3, increased Kv 4.3/KChIP2b channel currents. (PMID:15578212)
• Co-expression of DPPX in addition to Kv4.3 and KChIP2a produced similar current kinetics as in human ventricular myocytes (PMID:15890703)
• KCNE3 also inhibits currents generated by Kv4.3 in complex with the accessory subunit KChIP2 (PMID:16782062)
• the mechanisms involved in Syn1A-K(v) interactions vary significantly between K(v) channels, thus providing a wide scope for Syn1A modulation of exocytosis and membrane excitability (PMID:17506992)
• Kv4.3 regulates angiotensin type 1 receptor signaling to the small G-protein Rap-1 (PMID:17725712)
• KCND3 mutations were not found to directly cause long QT syndrome. (PMID:18052691)
• c-Src-induced Kv4.3 channel activation involves their association in a macromolecular complex (PMID:18620005)
• NO and NO donors inhibited I(Kv4.3) in a concentration- and voltage-dependent manner. (PMID:18678642)
• SAP97 is a major partner for surface expression and CaMKII-dependent regulation of cardiac Kv4.2 and kv4.3 channels. (PMID:19213956)
• Down-regulated atrial KChIP2 and Kv4.3 mRNA expressions in rheumatic heart disease patients with chronic atrial fibrillation might be one of the molecular bases responsible for the down-regulation of the I(to) current density of AF. (PMID:19927631)
• N-linked glycosylation of DPP10 plays an important role in modulating Kv4.3 channel/KCHIP2 complex activities. (PMID:20354865)
• KChIP4a functions to promote tetrameric assembly and enhance surface expression of Kv4 channels. (PMID:20550899)
• The I(to) activator NS5806 modified Kv4.3/KChIP2 gating in several ways that inhibit current. (PMID:20649599)
• our findings suggest that KChIP1 interacts with Kv4.3 in interneurons at the stratum lacunosum-moleculare/radiatum junction (PMID:21129448)
• Kv4.3 macromolecular complex and regulators of KCND3 expression is needed to elucidate the role of the Ito current in the pathogenesis of BrS and other J-wave syndromes. (PMID:21349352)
• The “structurally minimal” isoform KChIP2d modulates recovery of K(v)4.3 N-terminal deletion mutant Delta2-39. (PMID:21422811)
• Deep insights into the mechanism of the regulation of Kv4.3 K channels and the role of Kv4.3 K channels in cell death. (PMID:22023388)
• Human atrial I(to) and cloned hKv4.3 channels are modulated by EGFR kinase via phosphorylation of the Y136 residue and by Src-family kinases via phosphorylation of the Y108 residue. (PMID:22198508)
• KCND3 may serve as a rare genetic substrate in the pathogenesis of autopsy-negative sudden unexplained death (SUD) but not sudden infant death syndrome (SIDS) cases. (PMID:22457051)
• expression of the sodium (SCN5A) and potassium (KCND3) channels as well as the fibrosis content in the ventricles of heart failure and of non-diseased hearts under different post-mortem intervals (PMID:23036686)
• This study demonistrated that Mutations in KCND3 cause spinocerebellar ataxia type 22 in chinese and japanese. (PMID:23280837)
• This study demonistrated that KCND3 mutations cause SCA19 by impaired protein maturation and/or reduced channel function (PMID:23280838)
• The biophysical characteristics of Kv4.3 channels are strongly dependent on temperature. (PMID:23291429)
• Report a KV4.3 gain-of-function mutation in early-onset persistent lone atrial fibrillation. (PMID:23400760)
• findings indicate mutations in KCND3 are not a common cause of disease among rarer types of European cerebellar ataxia; however 2 variants were identified in the SCA cases: p.L450F and p.P614S; mutations in KCND3 can cause 2 allelic disorders, SCA19/22 and Brugada syndrome which may co-occur (PMID:23963749)
• Kv4.3 K(+) channel is involved in heart hypertrophy/heart failure independently of its electric function.[review] (PMID:24762397)
• These results indicate that Kv4.3 is likely the target of discrepin and highlight the importance of the basic residue K13, located in the alpha-helix of the toxin, for current blockage. (PMID:24845726)
• Demonstrate SEMA3A as a naturally occurring protein that selectively inhibits Kv4.3 and SEMA3A as a possible Brugada syndrome susceptibility gene through a Kv4.3 gain-of-function mechanism. (PMID:24963029)
• the interaction of DPP10a, expressed in human atrium, with Kv4.3 channels generates a sustained current component of Ito, which may affect late repolarization phase of atrial action potentials. (PMID:25600224)
• Altered Kv4.3 channel localization and/or functioning resulting from SCA19/22 mutations may lead to Purkinje cell loss, neurodegeneration and ataxia. (PMID:25854634)
• mutations cause a gainoffunction of KV4.3/KChIP2encoded channels by increasing membrane protein expression and slowing channel inactivation. (PMID:26016905)
• Mefloquine is a concentration-dependent Ito and hKv4.3 channel blocker. (PMID:26216464)
• The alpha subunit of Ito Kv4.3 can interact with and modify the localization of the alpha subunit of IKr hERG, thus providing potentially novel insights into the molecular mechanism of the malignant ventricular arrhythmia in heart failure. (PMID:29259226)
• The S248R and R250T mutations of SCN1Bbeta gene caused gain-of-function of Ito by associated with Kv4.3, which maybe underlie the early repolarization syndrome (ERS) phenotype of the probands. (PMID:30160358)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	kcnd3	ENSDARG00000056101
mus_musculus	Kcnd3	ENSMUSG00000040896
rattus_norvegicus	Kcnd3	ENSRNOG00000014686
drosophila_melanogaster	Shal	FBGN0005564

Paralogs (31): KCNG1 (ENSG00000026559), KCNQ1 (ENSG00000053918), KCNQ2 (ENSG00000075043), KCND1 (ENSG00000102057), KCNA7 (ENSG00000104848), KCNA1 (ENSG00000111262), KCNC4 (ENSG00000116396), KCNQ4 (ENSG00000117013), 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), KCNA3 (ENSG00000177272), KCNA2 (ENSG00000177301), KCNG2 (ENSG00000178342), KCNA4 (ENSG00000182255), KCNB2 (ENSG00000182674), KCNQ3 (ENSG00000184156), KCND2 (ENSG00000184408), KCNQ5 (ENSG00000185760)

Protein

Protein identifiers

A-type voltage-gated potassium channel KCND3 — Q9UK17 (reviewed: Q9UK17)

Alternative names: Potassium voltage-gated channel subfamily D member 3, Voltage-gated potassium channel subunit Kv4.3

All UniProt accessions (1): Q9UK17

UniProt curated annotations — full annotation on UniProt →

Function. Pore-forming (alpha) subunit of voltage-gated A-type potassium channels that mediates transmembrane potassium transport in excitable membranes, in brain and heart. In cardiomyocytes, may generate the transient outward potassium current I(To). In neurons, may conduct the transient subthreshold somatodendritic A-type potassium current (ISA). Kinetics properties are characterized by fast activation at subthreshold membrane potentials, rapid inactivation, and quick recovery from inactivation. Channel properties are modulated by interactions with regulatory subunits. Interaction with the regulatory subunits KCNIP1 or KCNIP2 modulates the channel gating kinetics namely channel activation and inactivation kinetics and rate of recovery from inactivation. Likewise, interaction with DPP6 modulates the channel gating kinetics namely channel activation and inactivation kinetics.

Subunit / interactions. Homotetramer. Heterotetramer with KCND2. Associates with the regulatory subunits KCNIP3 and KCNIP4. Interacts with KCNE1, KCNE2, SCN1B and KCNAB1 and DLG1. Component of heteromultimeric potassium channels. Identified in potassium channel complexes containing KCND1, KCND2, KCND3, KCNIP1, KCNIP2, KCNIP3, KCNIP4, DPP6 and DPP10. Interacts with KCNIP1; each KCNIP1 monomer interacts with two adjacent KCND3 subunits, through both the N-terminal inactivation ball of a KCND3 subunit and a C-terminal helix from the adjacent KCND3 subunit, clamping them together; this interaction stabilizes the tetrameric form and modulates the channel gating kinetics namely channel activation and inactivation kinetics and rate of recovery from inactivation. Interacts with DPP6; this interaction modulates the channel gating kinetics namely channel activation and inactivation kinetics and rate of recovery from inactivation. Interacts with KCNIP2; each KCNIP2 monomer interacts with two adjacent KCND3 subunits, through both the N-terminal inactivation ball of a KCND3 subunit and a C-terminal helix from the adjacent KCND3 subunit, clamping them together; this interaction modulates the channel gating kinetics.

Subcellular location. Cell membrane. Sarcolemma. Cell projection. Dendrite.

Tissue specificity. Highly expressed in heart and brain, in particular in cortex, cerebellum, amygdala and caudate nucleus. Detected at lower levels in liver, skeletal muscle, kidney and pancreas.

Post-translational modifications. Regulated through phosphorylation at Ser-569 by CaMK2D.

Disease relevance. Spinocerebellar ataxia 19 (SCA19) [MIM:607346] A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA19 is a relatively mild, cerebellar ataxic syndrome with cognitive impairment, pyramidal tract involvement, tremor and peripheral neuropathy, and mild atrophy of the cerebellar hemispheres and vermis. The disease is caused by variants affecting the gene represented in this entry. Brugada syndrome 9 (BRGDA9) [MIM:616399] A tachyarrhythmia characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs, the individual will faint and may die in a few minutes if the heart is not reset. The gene represented in this entry may be involved in disease pathogenesis.

Domain organisation. Two N-terminal domains regulate binding to and modulation by KCNIP1.

Similarity. Belongs to the potassium channel family. D (Shal) (TC 1.A.1.2) subfamily. Kv4.3/KCND3 sub-subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UK17-1	1, KCND3L, Long	yes
Q9UK17-2	2, KCND3S, Short

RefSeq proteins (4): NP_001365898, NP_001365899, NP_004971, NP_751948 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000210	BTB/POZ_dom	Domain
IPR003131	T1-type_BTB	Domain
IPR003968	K_chnl_volt-dep_Kv	Family
IPR003975	K_chnl_volt-dep_Kv4	Family
IPR004056	K_chnl_volt-dep_Kv4.3	Family
IPR005821	Ion_trans_dom	Domain
IPR011333	SKP1/BTB/POZ_sf	Homologous_superfamily
IPR021645	Shal-type_N	Domain
IPR024587	K_chnl_volt-dep_Kv4_C	Domain
IPR027359	Volt_channel_dom_sf	Homologous_superfamily
IPR028325	VG_K_chnl	Family

Pfam: PF00520, PF02214, PF11601, PF11879

Catalyzed reactions (Rhea), 1 shown:

• K(+)(in) = K(+)(out) (RHEA:29463)

UniProt features (98 total): helix 24, sequence variant 13, strand 10, binding site 8, sequence conflict 8, topological domain 7, transmembrane region 6, region of interest 6, turn 5, modified residue 4, intramembrane region 2, compositionally biased region 2, chain 1, short sequence motif 1, splice variant 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
1S1G	X-RAY DIFFRACTION	2.6
7W6S	ELECTRON MICROSCOPY	2.8
7W3Y	ELECTRON MICROSCOPY	3
2NZ0	X-RAY DIFFRACTION	3.2
7W6N	ELECTRON MICROSCOPY	3.4
7W6T	ELECTRON MICROSCOPY	3.85

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UK17-F1	71.32	0.35

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 (8): 104 (in chain b); 110 (in chain d); 131 (in chain b); 132 (in chain b); 367; 368; 369; 370

Post-translational modifications (4): 153, 459, 569, 585

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-1296072	Voltage gated Potassium channels
R-HSA-5576894	Phase 1 - inactivation of fast Na+ channels
R-HSA-112316	Neuronal System
R-HSA-1296071	Potassium Channels
R-HSA-397014	Muscle contraction
R-HSA-5576891	Cardiac conduction

MSigDB gene sets: 285 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, RNGTGGGC_UNKNOWN, MODULE_52, BENPORATH_ES_WITH_H3K27ME3, GOBP_CIRCULATORY_SYSTEM_PROCESS, REACTOME_VOLTAGE_GATED_POTASSIUM_CHANNELS, JAEGER_METASTASIS_DN, REACTOME_POTASSIUM_CHANNELS, ENK_UV_RESPONSE_KERATINOCYTE_UP, MODULE_45, MODULE_64, TGACCTY_ERR1_Q2, MODULE_16, GGGTGGRR_PAX4_03, GOBP_MONOATOMIC_CATION_TRANSPORT

GO Biological Process (17): action potential (GO:0001508), potassium ion transport (GO:0006813), muscle contraction (GO:0006936), chemical synaptic transmission (GO:0007268), regulation of heart contraction (GO:0008016), protein homooligomerization (GO:0051260), protein tetramerization (GO:0051262), potassium ion transmembrane transport (GO:0071805), membrane repolarization (GO:0086009), membrane repolarization during cardiac muscle cell action potential (GO:0086013), regulation of heart rate by cardiac conduction (GO:0086091), potassium ion export across plasma membrane (GO:0097623), membrane repolarization during ventricular cardiac muscle cell action potential (GO:0098915), ventricular cardiac muscle cell membrane repolarization (GO:0099625), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085)

GO Molecular Function (8): A-type (transient outward) potassium channel activity (GO:0005250), metal ion binding (GO:0046872), voltage-gated potassium channel activity involved in cardiac muscle cell action potential repolarization (GO:0086008), monoatomic ion channel activity (GO:0005216), voltage-gated potassium channel activity (GO:0005249), potassium channel activity (GO:0005267), protein binding (GO:0005515), voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization (GO:1902282)

GO Cellular Component (13): plasma membrane (GO:0005886), voltage-gated potassium channel complex (GO:0008076), sarcolemma (GO:0042383), neuronal cell body (GO:0043025), dendritic spine (GO:0043197), postsynaptic membrane (GO:0045211), Kv4.3-KChIP1 channel complex (GO:0071196), GABA-ergic synapse (GO:0098982), postsynaptic specialization membrane (GO:0099634), membrane (GO:0016020), dendrite (GO:0030425), monoatomic ion channel complex (GO:0034702), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Potassium Channels	1
Cardiac conduction	1
Neuronal System	1
Muscle contraction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of membrane potential	2
protein complex oligomerization	2
cardiac muscle cell membrane repolarization	2
membrane repolarization during cardiac muscle cell action potential	2
transport	2
postsynapse	2
synaptic membrane	2
cellular anatomical structure	2
metal ion transport	1
muscle system process	1
anterograde trans-synaptic signaling	1
heart contraction	1
regulation of blood circulation	1
potassium ion transport	1
monoatomic cation transmembrane transport	1
cardiac muscle cell action potential	1
membrane repolarization during action potential	1
regulation of heart rate	1
cardiac conduction	1
potassium ion transmembrane transport	1
export across plasma membrane	1
ventricular cardiac muscle cell action potential	1
ventricular cardiac muscle cell membrane repolarization	1
monoatomic ion transport	1
transmembrane transport	1
cellular process	1
outward rectifier potassium channel activity	1
cation binding	1
voltage-gated potassium channel activity	1
monoatomic ion transmembrane transporter activity	1
channel activity	1
potassium channel activity	1
voltage-gated monoatomic cation channel activity	1
monoatomic cation channel activity	1
potassium ion transmembrane transporter activity	1
binding	1
voltage-gated potassium channel activity involved in cardiac muscle cell action potential repolarization	1
membrane repolarization during ventricular cardiac muscle cell action potential	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

2158 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCND3	KCNIP2	Q9NS61	999
KCND3	KCNIP1	Q9NZI2	998
KCND3	DPP10	Q8N608	967
KCND3	KCNE3	Q9Y6H6	945
KCND3	KCNIP3	Q9Y2W7	927
KCND3	DPP6	P42658	924
KCND3	KCNIP4	Q6PIL6	922
KCND3	KCND2	Q9NZV8	882
KCND3	SCN1B	Q07699	837
KCND3	SCN5A	Q14524	819
KCND3	KCNH2	Q12809	799
KCND3	CACNA1C	Q13936	780
KCND3	KCNE2	Q9Y6J6	771
KCND3	NCS1	P36610	762
KCND3	KCNE5	Q9UJ90	756

IntAct

5 interactions, top by confidence:

A	B	Type	Score
KCNIP1	KCND3	psi-mi:“MI:0915”(physical association)	0.540
KCNIP1	KCND3	psi-mi:“MI:0407”(direct interaction)	0.540
KCND3	KCNIP1	psi-mi:“MI:0407”(direct interaction)	0.540
H2AC14	KCND3	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (52): KCND3 (Co-crystal Structure), KCND3 (Reconstituted Complex), SEMA3A (Affinity Capture-Western), KCND3 (Affinity Capture-RNA), KCND3 (Affinity Capture-Western), SCN1B (Affinity Capture-Western), KCND3 (Co-localization), KCND3 (Affinity Capture-Western), KCNH2 (Affinity Capture-Western), HSPA4 (Affinity Capture-Western), KCND3 (Affinity Capture-Western), HSP90AA1 (Affinity Capture-Western), KCND3 (Affinity Capture-Western), KCND3 (Proximity Label-MS), KCNA5 (Affinity Capture-Western)

ESM2 similar proteins: A0JPH4, A1DWM3, A4QN56, A6H8H5, B0UYT5, B3MG58, B3NSE1, B4GAP7, B4KR05, B4LPX5, B4QBN2, O18868, O60741, P08911, P11483, P15387, P20309, P41984, P59995, Q03717, Q0P5V9, Q14721, Q1LUC3, Q1LUQ4, Q291H8, Q4V887, Q4ZHA6, Q5BKX6, Q5VW38, Q62897, Q63099, Q63881, Q6ZSS7, Q8C145, Q8CBH5, Q8HYZ1, Q91WD0, Q92953, Q95167, Q95L11

Diamond homologs: A2BDX4, A4K2M4, A4K2N8, A4K2P6, A4K2Q6, A4K2R3, A4K2S2, A4K2T1, A4K2V2, A4K2W6, A4K2X4, A4K2Y2, A6H8H5, D4AD53, D4ADX7, G5EFC3, O18868, O35173, O35174, O73606, O88758, O88759, P10499, P15384, P15385, P15387, P15388, P16388, P16390, P17970, P17971, P17972, P22001, P22459, P22739, P25122, P48547, P59053, P59994, P59995

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
SRC	“up-regulates activity”	KCND3	phosphorylation
FGR	“up-regulates activity”	KCND3	phosphorylation
LYN	“up-regulates activity”	KCND3	phosphorylation
FYN	“up-regulates activity”	KCND3	phosphorylation
EGFR	“up-regulates activity”	KCND3	phosphorylation
KCND3	“down-regulates quantity”	potassium(1+)	relocalization
SRC_kinase_family	“up-regulates activity”	KCND3	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	15
Uncertain significance	300
Likely benign	307
Benign	25

Top pathogenic / likely-pathogenic (26)

Variant ID	HGVS	Classification
211216	NM_001378969.1(KCND3):c.1034G>T (p.Gly345Val)	Pathogenic
2581748	NM_001378969.1(KCND3):c.1201G>A (p.Val401Met)	Pathogenic
3600985	NM_001378969.1(KCND3):c.1201G>C (p.Val401Leu)	Pathogenic
3730865	NM_001378969.1(KCND3):c.916G>A (p.Gly306Ser)	Pathogenic
375399	NM_001378969.1(KCND3):c.1153T>C (p.Ser385Pro)	Pathogenic
626316	NM_001378969.1(KCND3):c.950G>A (p.Cys317Tyr)	Pathogenic
626317	NM_001378969.1(KCND3):c.1013T>A (p.Val338Glu)	Pathogenic
626318	NM_001378969.1(KCND3):c.1123C>T (p.Pro375Ser)	Pathogenic
626319	NM_001378969.1(KCND3):c.1130C>T (p.Thr377Met)	Pathogenic
66061	NM_001378969.1(KCND3):c.677TCT[1] (p.Phe227del)	Pathogenic
66062	NM_001378969.1(KCND3):c.1054A>C (p.Thr352Pro)	Pathogenic
1699176	NM_001378969.1(KCND3):c.905G>C (p.Arg302Pro)	Likely pathogenic
1699397	NM_001378969.1(KCND3):c.911C>T (p.Ser304Phe)	Likely pathogenic
2441718	NM_001378969.1(KCND3):c.1138G>T (p.Gly380Trp)	Likely pathogenic
2582302	NM_001378969.1(KCND3):c.1129A>G (p.Thr377Ala)	Likely pathogenic
2627229	NM_001378969.1(KCND3):c.848C>G (p.Ser283Cys)	Likely pathogenic
2627944	NM_001378969.1(KCND3):c.877_885dup (p.Arg296_Ile297insValPheArg)	Likely pathogenic
2684246	NM_001378969.1(KCND3):c.1094T>C (p.Met365Thr)	Likely pathogenic
372829	NM_001378969.1(KCND3):c.1195G>C (p.Val399Leu)	Likely pathogenic
4041484	NM_001378969.1(KCND3):c.1061T>A (p.Ile354Asn)	Likely pathogenic
4056391	NM_001378969.1(KCND3):c.905G>A (p.Arg302His)	Likely pathogenic
4082456	NM_001378969.1(KCND3):c.1154C>G (p.Ser385Cys)	Likely pathogenic
66064	NM_001378969.1(KCND3):c.1169G>A (p.Ser390Asn)	Likely pathogenic
816626	NM_001378969.1(KCND3):c.1076G>T (p.Trp359Leu)	Likely pathogenic
976123	NM_001378969.1(KCND3):c.869G>A (p.Arg290Gln)	Likely pathogenic
987028	NM_001378969.1(KCND3):c.910T>C (p.Ser304Pro)	Likely pathogenic

SpliceAI

1725 predictions. Top by Δscore:

Variant	Effect	Δscore
1:111778505:A:C	acceptor_gain	1.0000
1:111780218:GACTC:G	donor_loss	1.0000
1:111780219:ACTC:A	donor_loss	1.0000
1:111780220:CT:C	donor_loss	1.0000
1:111780221:TCAC:T	donor_loss	1.0000
1:111780222:CACAG:C	donor_loss	1.0000
1:111780223:A:AC	donor_gain	1.0000
1:111780223:A:T	donor_loss	1.0000
1:111780224:C:A	donor_loss	1.0000
1:111780224:C:CC	donor_gain	1.0000
1:111780224:CA:C	donor_gain	1.0000
1:111780224:CAG:C	donor_gain	1.0000
1:111780224:CAGT:C	donor_gain	1.0000
1:111780224:CAGTG:C	donor_gain	1.0000
1:111780310:GTGCC:G	acceptor_gain	1.0000
1:111780311:TGCC:T	acceptor_gain	1.0000
1:111780312:GCC:G	acceptor_gain	1.0000
1:111780313:CC:C	acceptor_gain	1.0000
1:111780313:CCC:C	acceptor_gain	1.0000
1:111780314:CC:C	acceptor_gain	1.0000
1:111780315:C:CC	acceptor_gain	1.0000
1:111780315:C:T	acceptor_gain	1.0000
1:111780318:G:C	acceptor_gain	1.0000
1:111780318:G:GC	acceptor_gain	1.0000
1:111786938:GCTTA:G	donor_loss	1.0000
1:111786939:CTTA:C	donor_loss	1.0000
1:111786940:TTA:T	donor_loss	1.0000
1:111786941:TA:T	donor_loss	1.0000
1:111786942:ACC:A	donor_loss	1.0000
1:111786943:C:CT	donor_loss	1.0000

AlphaMissense

4203 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:111786957:C:G	R419P	1.000
1:111786968:T:A	R415S	1.000
1:111786968:T:G	R415S	1.000
1:111786978:T:G	Q412P	1.000
1:111786985:A:C	Y410D	1.000
1:111786990:C:G	R408P	1.000
1:111786995:A:C	F406L	1.000
1:111786995:A:T	F406L	1.000
1:111786996:A:C	F406C	1.000
1:111786996:A:G	F406S	1.000
1:111786997:A:C	F406V	1.000
1:111786997:A:G	F406L	1.000
1:111786997:A:T	F406I	1.000
1:111786998:G:C	N405K	1.000
1:111786998:G:T	N405K	1.000
1:111787003:A:G	S404P	1.000
1:111787005:A:T	V403D	1.000
1:111787006:C:G	V403L	1.000
1:111787008:A:C	I402S	1.000
1:111787008:A:T	I402N	1.000
1:111787011:A:T	V401E	1.000
1:111787014:G:C	P400R	1.000
1:111787014:G:T	P400H	1.000
1:111787017:A:T	V399D	1.000
1:111787020:G:A	P398L	1.000
1:111787020:G:C	P398R	1.000
1:111787020:G:T	P398Q	1.000
1:111787021:G:A	P398S	1.000
1:111787023:A:C	L397R	1.000
1:111787023:A:G	L397P	1.000

dbSNP variants (sampled 300 via entrez): RS1000020708 (1:111846626 A>G), RS1000046671 (1:111802933 T>C), RS1000100702 (1:111910545 C>G), RS1000102948 (1:111977041 C>G,T), RS1000109030 (1:111972456 G>A), RS1000109842 (1:111931737 A>G), RS1000120711 (1:111936523 G>T), RS1000124931 (1:111868250 C>A,T), RS1000150352 (1:111882793 G>A), RS1000152958 (1:111887982 G>C), RS1000154025 (1:111977671 A>G), RS1000157656 (1:111965730 A>G,T), RS1000168551 (1:111881638 G>A), RS1000182933 (1:111807015 A>G,T), RS1000192191 (1:111850372 G>A)

Disease associations

OMIM: gene MIM:605411 | disease phenotypes: MIM:607346, MIM:616399, MIM:601144

GenCC curated gene-disease

Disease	Classification	Inheritance
spinocerebellar ataxia type 19/22	Strong	Autosomal dominant
neurodevelopmental disorder	Strong	Autosomal dominant
Brugada syndrome 9	Limited	Autosomal dominant
Brugada syndrome 1	Disputed Evidence	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Brugada syndrome 1	Disputed	AD

Mondo (9): spinocerebellar ataxia type 19/22 (MONDO:0011819), hereditary ataxia (MONDO:0100309), Brugada syndrome 9 (MONDO:0014621), Brugada syndrome (MONDO:0015263), epilepsy (MONDO:0005027), dilated cardiomyopathy (MONDO:0005021), intellectual disability (MONDO:0001071), Brugada syndrome 1 (MONDO:0011001), neurodevelopmental disorder (MONDO:0700092)

Orphanet (5): Hereditary ataxia (Orphanet:183518), Spinocerebellar ataxia type 19/22 (Orphanet:98772), Brugada syndrome (Orphanet:130), Dilated cardiomyopathy (Orphanet:217604), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

49 total (30 of 49 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000020	Urinary incontinence
HP:0000602	Ophthalmoplegia
HP:0000639	Nystagmus
HP:0000651	Diplopia
HP:0001152	Saccadic smooth pursuit interruptions
HP:0001251	Ataxia
HP:0001260	Dysarthria
HP:0001265	Hyporeflexia
HP:0001272	Cerebellar atrophy
HP:0001279	Syncope
HP:0001288	Gait disturbance
HP:0001336	Myoclonus
HP:0001347	Hyperreflexia
HP:0001350	Slurred speech
HP:0001649	Tachycardia
HP:0001657	Prolonged QT interval
HP:0001663	Ventricular fibrillation
HP:0001695	Cardiac arrest
HP:0001962	Palpitations
HP:0002015	Dysphagia
HP:0002066	Gait ataxia
HP:0002070	Limb ataxia
HP:0002073	Progressive cerebellar ataxia
HP:0002078	Truncal ataxia
HP:0002136	Broad-based gait
HP:0002172	Postural instability
HP:0002174	Postural tremor
HP:0002311	Incoordination
HP:0002396	Cogwheel rigidity

GWAS associations

287 associations (top):

Study	Trait	p-value
GCST001523_7	Visceral adipose tissue adjusted for BMI	1.000000e-06
GCST001538_7	Immune reponse to smallpox (secreted IFN-alpha)	9.000000e-10
GCST001559_3	Early cardiac repolarization	8.000000e-06
GCST002431_2	Response to radiotherapy in cancer (late toxicity)	6.000000e-16
GCST002457_1	P wave duration	8.000000e-11
GCST004373_4	Atrial fibrillation	4.000000e-15
GCST004824_1	P wave terminal force	6.000000e-19
GCST004824_7	P wave terminal force	3.000000e-20
GCST006061_134	Atrial fibrillation	4.000000e-09
GCST006061_211	Atrial fibrillation	2.000000e-12
GCST006414_55	Atrial fibrillation	1.000000e-14
GCST007226_12	PR interval	1.000000e-13
GCST007936_3	Medication use (opioids)	3.000000e-08
GCST008512_2	Multisite chronic pain	2.000000e-09
GCST008991_2	Early cardiac repolarization	8.000000e-12
GCST010321_100	PR interval	7.000000e-49
GCST010346_4	TPE interval (resting)	9.000000e-10
GCST010796_1074	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-40
GCST010796_2332	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST010796_2859	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-08
GCST010796_2860	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-09
GCST010796_2861	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_2862	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-08
GCST010796_2863	Electrocardiogram morphology (amplitude at temporal datapoints)	7.000000e-12
GCST010796_2864	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-12
GCST010796_2865	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-14
GCST010796_2866	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-14
GCST010796_2867	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-13
GCST010796_2868	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-12
GCST010796_2869	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-11

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004645	response to vaccine
EFO:0004873	cytokine measurement
EFO:0004885	early cardiac repolarization measurement
EFO:0005094	P wave duration
EFO:0008379	P wave terminal force measurement
EFO:0004462	PR interval
EFO:0009937	Opioid use measurement
EFO:0010100	multisite chronic pain
EFO:0004644	TPE interval measurement
EFO:0004327	electrocardiography
EFO:0004530	triglyceride measurement
EFO:0005658	response to selective serotonin reuptake inhibitor

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D053840	Brugada Syndrome	C14.280.067.322; C14.280.123.250; C16.320.100
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D004827	Epilepsy	C10.228.140.490
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
C531684	Hereditary spinal ataxia (supp.)
C537198	Spinocerebellar ataxia 19 (supp.)
C542540	Spinocerebellar ataxia 22 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL1964 (SINGLE PROTEIN), CHEMBL2362996 (PROTEIN FAMILY), CHEMBL3885598 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

10 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 178,961 (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
CHEMBL1175	DULOXETINE	4	28,527
CHEMBL1323	DARUNAVIR	4	15,382
CHEMBL1346	DARIFENACIN	4	8,259
CHEMBL1382	TOLTERODINE	4	13,460
CHEMBL1520	VARDENAFIL	4	21,078
CHEMBL1621	PALIPERIDONE	4	1,701
CHEMBL1734	SOLIFENACIN	4	296
CHEMBL434394	NEBIVOLOL	4	9,645
CHEMBL535	SUNITINIB	4	79,020
CHEMBL550348	DEFERASIROX	4	1,593

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 (7 total), top 7:

Ligand	Action	Affinity	Parameter
phrixotoxin 1	Channel blocker	8.7	pIC50
nicotine	Channel blocker	7.4	pIC50
phrixotoxin 2	Channel blocker	7.0	pIC50
sibutramine	Channel blocker	4.7	pIC50
bupivacaine	Channel blocker	4.0	pIC50
riluzole	Gating inhibitor	3.9	pIC50
fampridine	Channel blocker	2.4	pIC50

ChEMBL bioactivities

8 potent at pChembl≥5 of 20 total, top 8 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
5.85	IC50	1400	nM	CHEMBL44297
5.64	IC50	2300	nM	CHEMBL4065169
5.41	IC50	3870	nM	CHEMBL569185
5.24	IC50	5800	nM	CHEMBL2042163
5.08	IC50	8300	nM	CHEMBL4104525
5.03	IC50	9300	nM	ACACETIN

PubChem BioAssay actives

7 with measured affinity, of 142 total; 6 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
N-[(3S,4R)-6-cyano-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]-N-methylethanesulfonamide	161268: The inhibitory concentration for 50% was measured on potassium channel complex	ic50	1.4000	uM
N-[6-[(1S)-1-(4-fluorophenyl)-2,2-dipyridin-3-ylethyl]-2-pyridinyl]methanesulfonamide	1437183: Inhibition of Kv4.3 (unknown origin) assessed as reduction in transient outward potassium current by high throughput clamp method	ic50	2.3000	uM
N-[(4R)-4-(4-methoxyphenyl)-3-[2-(4-methoxyphenyl)ethyl]-2-oxoimidazolidin-1-yl]methanesulfonamide	441884: Inhibition of Kv4.3 expressed in CHO cells by patch-clamp technique	ic50	3.8700	uM
[(7S)-5-(methoxymethyl)-7-(1-methylindol-2-yl)-2-(trifluoromethyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl]-[(2S)-2-(3-methyl-1,2-oxazol-5-yl)pyrrolidin-1-yl]methanone	667337: Inhibition of KV4.3 ion channel	ic50	5.8000	uM
(1R)-1-[2-(3,5-dichlorophenyl)-3-pyridinyl]-2,2-dipyridin-3-ylethanol	1437183: Inhibition of Kv4.3 (unknown origin) assessed as reduction in transient outward potassium current by high throughput clamp method	ic50	8.3000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects expression, affects methylation, decreases expression, increases methylation	3
Aflatoxin B1	decreases expression, decreases methylation, increases methylation	3
Valproic Acid	increases expression	2
aristolochic acid I	decreases expression	1
methyleugenol	decreases expression	1
bisphenol A	decreases methylation	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
chelerythrine	decreases activity, decreases reaction	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1
diallyl trisulfide	affects binding, decreases activity	1
CGP 52608	affects binding, increases reaction	1
clothianidin	decreases expression	1
incobotulinumtoxinA	increases expression	1
Vorinostat	decreases expression	1
Acetaminophen	decreases expression	1
Cadmium	decreases expression	1
Calcitriol	increases expression, affects cotreatment	1
Doxorubicin	decreases expression	1
Fluoxetine	decreases activity	1
Lipopolysaccharides	increases expression, decreases reaction	1
Methapyrilene	increases methylation	1
Phenylephrine	decreases reaction, affects cotreatment, affects response to substance, decreases activity	1
Testosterone	affects cotreatment, increases expression	1
Tetradecanoylphorbol Acetate	decreases activity	1
Tobacco Smoke Pollution	decreases expression	1
Verapamil	decreases activity	1
Antirheumatic Agents	decreases expression	1

ChEMBL screening assays

118 unique, capped per target: 55 binding, 44 functional, 12 admet, 7 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1039578	Binding	Inhibition of Kv4.3 expressed in CHO cells by patch-clamp technique	Selective Kv1.5 blockers: development of (R)-1-(methylsulfonylamino)-3-[2-(4-methoxyphenyl)ethyl]-4-(4-methoxyphenyl)-2-imidazolidinone (KVI-020/WYE-160020) as a potential treatment for atrial arrhythmia. — J Med Chem
CHEMBL3430534	Functional	Inhibition of transient outward potassium current (Ito) current in Chinese Hamster Ovary (CHO) K1 cells expressing human Kv4.3 measured using IonWorks Quattro automated patch clamp platform	Prediction of Thorough QT study results using action potential simulations based on ion channel screens. — J Pharmacol Toxicol Methods
CHEMBL4393837	ADMET	Inhibition of human Kv4.3 by Ion-work electrophysiology assay	Discovery and Early Clinical Development of an Inhibitor of 5-Lipoxygenase Activating Protein (AZD5718) for Treatment of Coronary Artery Disease. — J Med Chem

Cellosaurus cell lines

9 cell lines: 4 induced pluripotent stem cell, 3 spontaneously immortalized cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A3ZI	ZZUi021-A	Induced pluripotent stem cell	Male
CVCL_C0Y4	B’SYS CHO Kv4.3	Spontaneously immortalized cell line	Female
CVCL_C0Y5	B’SYS CHO Kv4.3/KChiP2	Spontaneously immortalized cell line	Female
CVCL_D1K8	PrecisION hKv4.3/KCHiP1-CHO	Spontaneously immortalized cell line	Female
CVCL_D1K9	PrecisION hKv4.3/KChiP2-HEK	Transformed cell line	Female
CVCL_E4QA	KOLF2.1J KCND3 1.2kbdel DEL/DEL	Induced pluripotent stem cell	Male
CVCL_E5JN	HEK293 Kv4.3	Transformed cell line	Female
CVCL_XD53	IBMS-iPSC-046-06	Induced pluripotent stem cell	Female
CVCL_XD54	IBMS-iPSC-047-03	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00702117	PHASE4	COMPLETED	Ajmaline Utilization in the Diagnosis and Treatment of Cardiac Arrhythmias
NCT00004637	PHASE4	COMPLETED	Double-Blind, Placebo-Controlled Trial of Vitamin E as Add-on Therapy for Children With Epilepsy
NCT00043914	PHASE4	COMPLETED	Measurement Of Serum Levels Of Two Antiepileptic Drugs During Conversion In Patients With Epilepsy
NCT00132223	PHASE4	UNKNOWN	Effects on the Diagnostic Accuracy of Magnetic Imaging Angiographies of the Supra-Aortic Vessels by Three Different Magnetic Resonance Contrast Agents in Patients
NCT00133081	PHASE4	UNKNOWN	Study to Improve the Treatment of Epilepsy (SITE)
NCT00137709	PHASE4	UNKNOWN	Hormone Profiles in Adults With Newly Diagnosed Epilepsy
NCT00154076	PHASE4	COMPLETED	A Multicenter Comparative Trial of Zonisamide and Topiramate as Initial Monotherapy in Untreated Epilepsies
NCT00165828	PHASE4	TERMINATED	Efficacy and Safety of an add-on Treatment With Zonisamide in Adults With Focal Epileptic Seizures With or Without Secondary Generalization
NCT00181116	PHASE4	COMPLETED	Levetiracetam for Benign Rolandic Epilepsy
NCT00207935	PHASE4	COMPLETED	Use of Sustained Release Antiepileptic Medication (Depakote® ER) for Pediatric Epilepsy in a Mental Retardation/Developmental Disorder Population
NCT00215592	PHASE4	COMPLETED	Open Label, Zonegran (Zonisamide) In Partial Onset Seizures
NCT00266604	PHASE4	COMPLETED	A Study to Evaluate the Dosing, Effectiveness and Safety of Topiramate for the Treatment of Epilepsy
NCT00288639	PHASE4	COMPLETED	Lyrica (Pregabalin) Administered as an Add-on Therapy for Partial Seizures (LEADER).
NCT00312676	PHASE4	UNKNOWN	Compare Tolerability of an Overnight Switch to Gradual Switch Between Two Different Forms of Depakote
NCT00323947	PHASE4	COMPLETED	Methylphenidate for Treating Attention Deficit Hyperactivity Disorder in Children With Both ADHD and Epilepsy
NCT00385411	PHASE4	COMPLETED	Study of Valproate in Young Patients Suffering From Epilepsy
NCT00522418	PHASE4	TERMINATED	Study Comparing Best Medical Practice With or Without VNS Therapy in Pharmacoresistant Partial Epilepsy Patients
NCT00537940	PHASE4	COMPLETED	Comparative Study Of Pregabalin And Gabapentin As Adjunctive Therapy In Subjects With Partial Seizures
NCT00552526	PHASE4	UNKNOWN	Ketogenic Diet vs.Antiepileptic Drug Treatment in Drug Resistant Epilepsy
NCT00564915	PHASE4	COMPLETED	RCT of the Efficacy of the Ketogenic Diet in the Treatment of Epilepsy
NCT00571155	PHASE4	COMPLETED	Trial of Levetiracetam in Patients With Primary Brain Tumors and Symptomatic Seizures Who Undergo Surgery
NCT00572195	PHASE4	COMPLETED	RNS® System LTT Study
NCT00610532	PHASE4	TERMINATED	Evaluating the Transporter Protein Inhibitor Probenecid In Patients With Epilepsy
NCT00630357	PHASE4	COMPLETED	Trial to Evaluate the Safety and Efficacy of Keppra After Conversion to Mono-therapy in Subjects With Partial Epilepsy
NCT00630630	PHASE4	COMPLETED	Study on Safety and Efficacy of Levetiracetam in the Adjunctive Treatment of Female Subjects With C1 Catamenial Epilepsy
NCT00630968	PHASE4	COMPLETED	S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00631150	PHASE4	COMPLETED	A Phase IV-Pharmacovigilance Study of Keppra Greece - S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00659958	PHASE4	COMPLETED	ZAGAL Study: Evaluating Effectiveness and Tolerability of Zonisamide as Adjunctive Therapy in Patients With Partial Onset Seizures Treated With Two Antiepileptic Drugs
NCT00713622	PHASE4	COMPLETED	Comparing The Effect On Cognition Of Adjunctive Therapy With Zonisamide Versus Sodium Valproate
NCT00807989	PHASE4	COMPLETED	The Efficacy and Safety of Low Dose Combination of LTG and VPA Compared to CBZ Monotherapy
NCT00832884	PHASE4	COMPLETED	The Safety of Intravenous Lacosamide
NCT00869622	PHASE4	COMPLETED	Antiepileptic Drugs and Osteoporotic Prevention Trial
NCT00896987	PHASE4	COMPLETED	Lamotrigine Cognitive Function Study in Adult Untreated Epilepsies
NCT00952081	PHASE4	COMPLETED	A Pilot Study to Evaluate Efficacy and Safety of Clevidipine in Neurosurgical Patients
NCT01118455	PHASE4	TERMINATED	Trial to Assess Vagus Nerve Stimulation Therapy vs. Anti-Epileptic Drug (AED) Treatment in Children With Refractory Seizures
NCT01127165	PHASE4	COMPLETED	Low and High Dose Zonisamide in Children as Monotherapy
NCT01127256	PHASE4	COMPLETED	Comparative Study of Zonisamide and Carbamazepine as an Initial Monotherapy: Efficacy and Safety Evaluation
NCT01140867	PHASE4	COMPLETED	Open-label, Multi-center Trial of Zonisamide as Adjunctive Therapy in Patients With Uncontrolled Partial Epilepsy