KCNJ5

Summary

KCNJ5 (potassium inwardly rectifying channel subfamily J member 5, HGNC:6266) is a protein-coding gene on chromosome 11q24.3, encoding G protein-activated inward rectifier potassium channel 4 (P48544). Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it.

This gene encodes an integral membrane protein which belongs to one of seven subfamilies of inward-rectifier potassium channel proteins called potassium channel subfamily J. The encoded protein is a subunit of the potassium channel which is homotetrameric. It is controlled by G-proteins and has a greater tendency to allow potassium to flow into a cell rather than out of a cell. Naturally occurring mutations in this gene are associated with aldosterone-producing adenomas.

Source: NCBI Gene 3762 — RefSeq curated summary.

At a glance

• Gene–disease (curated): familial hyperaldosteronism type III (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 19
• Clinical variants (ClinVar): 533 total — 5 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 93
• Druggable target: yes
• MANE Select transcript: NM_000890

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6266
Approved symbol	KCNJ5
Name	potassium inwardly rectifying channel subfamily J member 5
Location	11q24.3
Locus type	gene with protein product
Status	Approved
Aliases	Kir3.4, CIR, KATP1, GIRK4, LQT13
Ensembl gene	ENSG00000120457
Ensembl biotype	protein_coding
OMIM	600734
Entrez	3762

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 9 protein_coding

ENST00000338350, ENST00000529694, ENST00000533599, ENST00000904658, ENST00000957736, ENST00000957737, ENST00000957738, ENST00000957739, ENST00000957740

RefSeq mRNA: 2 — MANE Select: NM_000890 NM_000890, NM_001354169

CCDS: CCDS8479

Canonical transcript exons

ENST00000529694 — 3 exons

Exon	Start	End
ENSE00001374212	128911264	128912210
ENSE00001379580	128916409	128921163
ENSE00002185882	128891356	128891721

Expression profiles

Bgee: expression breadth ubiquitous, 175 present calls, max score 96.69.

FANTOM5 (CAGE): breadth broad, TPM avg 1.7835 / max 122.0933, expressed in 333 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
117567	1.1256	265
117568	0.4154	147
117569	0.2425	94

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	96.69	gold quality
endothelial cell	CL:0000115	92.32	gold quality
adrenal cortex	UBERON:0001235	90.91	gold quality
right adrenal gland	UBERON:0001233	90.89	gold quality
left adrenal gland	UBERON:0001234	90.85	gold quality
left adrenal gland cortex	UBERON:0035825	90.58	gold quality
adrenal gland	UBERON:0002369	89.75	gold quality
right adrenal gland cortex	UBERON:0035827	89.54	gold quality
tendon of biceps brachii	UBERON:0008188	89.27	silver quality
heart right ventricle	UBERON:0002080	85.15	gold quality
mucosa of paranasal sinus	UBERON:0005030	85.11	gold quality
adrenal tissue	UBERON:0018303	83.93	gold quality
myocardium	UBERON:0002349	82.98	silver quality
seminal vesicle	UBERON:0000998	82.11	gold quality
medial globus pallidus	UBERON:0002477	80.95	silver quality
superficial temporal artery	UBERON:0001614	79.38	gold quality
globus pallidus	UBERON:0001875	78.87	silver quality
cardiac atrium	UBERON:0002081	78.85	gold quality
pituitary gland	UBERON:0000007	78.66	gold quality
sperm	CL:0000019	78.53	gold quality
body of pancreas	UBERON:0001150	78.27	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	78.22	gold quality
right atrium auricular region	UBERON:0006631	78.08	gold quality
male germ cell	CL:0000015	77.75	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	77.26	gold quality
vena cava	UBERON:0004087	77.18	gold quality
cerebellar vermis	UBERON:0004720	77.09	gold quality
inferior olivary complex	UBERON:0002127	77.02	gold quality
cardia of stomach	UBERON:0001162	76.78	gold quality
germinal epithelium of ovary	UBERON:0001304	76.52	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	13.08
E-GEOD-99795	no	1.47

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

53 targeting KCNJ5, 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-4533	100.00	69.48	2758
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-4420	99.82	70.08	1624
HSA-MIR-181B-2-3P	99.81	70.06	1646
HSA-MIR-181B-3P	99.81	70.06	1646
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-4677-3P	99.49	67.91	1246
HSA-MIR-4728-3P	99.47	68.94	981
HSA-MIR-6839-3P	99.39	68.86	1301
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-4721	99.26	66.05	818
HSA-MIR-149-5P	99.25	67.16	1315
HSA-MIR-6799-5P	99.14	65.72	2093
HSA-MIR-29A-5P	99.08	68.59	1813

Literature-anchored findings (GeneRIF, showing 40)

• GIRK channels are important functional effectors of the P2Y(12) receptor in human platelets. (PMID:15142872)
• K(ATP) channels have important functions including homeostasis maintenance and vascular tone regulation under physiological conditions (PMID:15694835)
• GIRK1 and GIRK2 channels, but not GIRK3 or GIRK4, may may activate signaling pathways in development of lung cancer (PMID:16109170)
• This may explain the lack of clear clinical manifestations and further studies are necessary to elucidate if mutations in Kir3.4 are predisposing AF. (PMID:17967416)
• review the structure and function of ABC proteins and discuss SUR, its regulation of the K(ATP) channel, and its role in cardiovascular disease. (PMID:18239147)
• No genetic association between polymorphisms in the kainate-type glutamate receptor gene, GRIK4, and schizophrenia in the Chinese population. (PMID:18289755)
• Sar 1 H79G and Rab 1 S25N mutants efficiently blocked the plasma membrane trafficking of the Kir3.1/Kir3.4 complex. (PMID:19135528)
• the frequency of genotype and allele in the C171T and G810T polymorphisms of Kir3.4 (K+ channel potassium inwardly-rectifier) are significantly different between lone paroxysmal Atrial fibrillation patients than in control subjects (PMID:19208499)
• loss of KATP channel activity may protect against streptozotocin-induced diabetes in vivo (PMID:19805912)
• We identified several known single nucleotide polymorphisms in KCNJ3 and KCNJ5, but no mutations in either of the genes. (PMID:20110696)
• Our findings suggest a role for Kir3.4 in the etiology of LQTS. (PMID:20560207)
• identified 2 somatic mutations in and near selectivity filter of KCNJ5 channel in aldosterone-producing adrenal adenomas and an inherited KCNJ5 mutation producing increased Na(+) conductance in Mendelian form of aldosteronism and adrenal hyperplasia (PMID:21311022)
• Both genotype distribution and allele frequencies of the SNPs rs6590357 and rs7118824 in KCNJ5 significantly differed between the early-onset lone atrial fibrillation patients and control group. (PMID:21555883)
• The activation of atrial and ventricular K(ATP) channels enhances arrhythmogenicity, suggesting that such activation may contribute to reentrant arrhythmias in ischemic hearts. (PMID:21586291)
• This study is the first to identify the expression of GIRK2-4 subunits in human esophageal smooth muscle cells. (PMID:21637918)
• Mutations in KCNJ5 gene cause hyperaldosteronism (PMID:21659651)
• A new mutation in the KCNJ5 potassium channel is associated with familial hyperaldosteronism-III and is responsible for marked alterations of channel function. And it associated with a mild clinical and hormonal phenotype. (PMID:22203740)
• somatic KCNJ5 mutations are not restricted to large APAs (>2 cm), and their frequency in our unselected series suggests they are common and could be important in the molecular pathogenesis of many sporadic cases of APA. (PMID:22252394)
• younger age and higher aldosterone levels at diagnosis suggest that KCNJ5 mutations may be associated with a more florid phenotype of primary aldosteronism. (PMID:22275527)
• Data suggest that significant number of patients with aldosterone-producing adenoma (APA) have KCNJ5 mutations; KCNJ5 mRNA level is higher in APA with mutation; KCNJ5 mRNA level is higher in APA than in cortisol-producing adenoma/pheochromocytoma. (PMID:22278422)
• findings demonstrate variations in phenotypes and clinical outcome resulting from different mutations of the same amino acid in KCNJ5 and have implications for diagnosis and pathogenesis of primary aldosteronism with and without adrenal hyperplasia (PMID:22308486)
• Potassium channel mutant KCNJ5 T158A expression in HAC-15 cells increases aldosterone synthesis. (PMID:22315453)
• Two somatic KCNJ5 mutations were identified in 16 human aldosterone producing adenomas, one of them is novel; both mutations result in a depolarization of current reversal potential and loss of channel selectivity (PMID:22323562)
• KCNJ5 mutations are common in aldosterone-producing adenomas, particularly those arising from zona fasiculata. The long-recognized heterogeneity among aldosterone-producing adenomas may have a genetic basis. (PMID:22442279)
• Sequencing of the KCNJ5 gene revealed a single, heterozygous guanine to thymine (G –> T) substitution at nucleotide position 470 (n.G470T), resulting in isoleucine (I) to serine (S) substitution at amino acid 157 (p.I157S). (PMID:22628607)
• KCNJ5 mutations are prevalent in aldosterone producing adenomas (APA). (PMID:22628608)
• An investigation into the GIRK4 genotypes revealed that each of the four common polymorphisms examined (rs2604204, rs4937391, rs6590367 and rs11221497) are significantly associated with metabolic syndrome in the Uygurian population,and this association may be influenced by age. (PMID:22645387)
• Hyaluronan export through plasma membranes depends on concurrent K+ efflux by K(ir) channels. (PMID:22701748)
• novel KCNJ5 mutation behaves like the three selectivity filter mutations previously reported in APAs depolarizing the cell and showing reduced cation selectivity (PMID:22743686)
• A-II appears to stimulate aldosterone secretion by depolarizing the membrane acting in part through the regulation of the expression and activity of Kir3.4. (PMID:22798349)
• Either of two somatic KCNJ5 mutations are highly prevalent and specific for aldosterone producing lesions (PMID:22848660)
• findings suggested that at least some aldosterone- and cortisol-co-secreting adrenal tumors have mutations of the KCNJ5 gene, suggesting the origin to be adrenal aldosterone-producing adenoma(APA), and pure APAs may show a high incidence of KCNJ5 mutations (PMID:22863749)
• Aldosterone-producing adenoma patients with the somatic KCNJ5 mutations showed a higher production of aldosterone than those without such mutations, which translates in a higher lateralization index. (PMID:23012392)
• GIRK4 gene polymorphisms may be associated with IR in Uygur ethnics from Xinjiang. The CC genotype of rs11221497 variant is a risk factor for insulin resistance. (PMID:23225057)
• Mutations in the KCNJ5 gene, which encodes the GIRK4 K+ channel, have been shown to be responsible for familial hyperaldosteronism type III and a consistent proportion of sporadic aldosterone-producing adenomas. [Review] (PMID:23229280)
• new insight into the pathogenesis of aldosterone-producing adenomas (APAs) and inherited primary aldosteronism; the role of mutations in the potassium channel KCNJ5 in these disorders (Review) (PMID:23318698)
• KCNJ5 mutations are not correlated with adrenal cortex remodeling in aldosterone producing adenoma (PMID:23376008)
• The genetic variant rs2604204 of KCNJ5 is associated with sporadic PA in Chinese males, suggesting that KCNJ5 may be involved in the pathogenesis of sporadic PA in these particular patients (PMID:23382865)
• KCNJ5 mutations are associated with better surgical outcome in patients diagnosed with adrenal gland neoplasms. (PMID:23778974)
• Kir3.4 potassium channel is expressed in the zona glomerulosa cell membrane and regulates aldosterone biosynthesis[review]. (PMID:23829355)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	kcnj5	ENSDARG00000061014
mus_musculus	Kcnj5	ENSMUSG00000032034
rattus_norvegicus	Kcnj5	ENSRNOG00000033796

Paralogs (15): KCNJ13 (ENSG00000115474), KCNJ8 (ENSG00000121361), KCNJ2 (ENSG00000123700), KCNJ1 (ENSG00000151704), KCNJ16 (ENSG00000153822), KCNJ6 (ENSG00000157542), KCNJ15 (ENSG00000157551), KCNJ9 (ENSG00000162728), KCNJ3 (ENSG00000162989), KCNJ4 (ENSG00000168135), KCNJ10 (ENSG00000177807), KCNJ14 (ENSG00000182324), KCNJ12 (ENSG00000184185), KCNJ11 (ENSG00000187486), KCNJ18 (ENSG00000260458)

Protein

Protein identifiers

G protein-activated inward rectifier potassium channel 4 — P48544 (reviewed: P48544)

Alternative names: Cardiac inward rectifier, Heart KATP channel, Inward rectifier K(+) channel Kir3.4, KATP-1, Potassium channel, inwardly rectifying subfamily J member 5

All UniProt accessions (2): A0A5J6E2W8, P48544

UniProt curated annotations — full annotation on UniProt →

Function. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. Can be blocked by external barium. This potassium channel is controlled by G proteins.

Subunit / interactions. Associates with KCNJ3/GIRK1 to form a G-protein-activated heteromultimer pore-forming unit. The resulting inward current is much larger. Associates with KCNJ6/GIRK2 to form a G-protein-activated heteromultimer pore-forming unit.

Subcellular location. Membrane.

Tissue specificity. Islets, exocrine pancreas and heart. Expressed in the adrenal cortex, particularly the zona glomerulosa.

Disease relevance. Long QT syndrome 13 (LQT13) [MIM:613485] A heart disorder characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress, and can present with a sentinel event of sudden cardiac death in infancy. The disease is caused by variants affecting the gene represented in this entry. Hyperaldosteronism, familial, 3 (HALD3) [MIM:613677] A form of hyperaldosteronism characterized by hypertension secondary to massive adrenal mineralocorticoid production. HALD3 patients present with childhood hypertension, elevated aldosteronism levels, and high levels of the hybrid steroids 18-oxocortisol and 18-hydroxycortisol. Hypertension and aldosteronism are not reversed by administration of exogenous glucocorticoids and patients require adrenalectomy to control hypertension. The disease is caused by variants affecting the gene represented in this entry. Somatic mutations in KCNJ5 have been found in aldosterone-producing adrenal adenomas and can be responsible for aldosteronism associated with cell autonomous proliferation. APAs are typically solitary, well circumscribed tumors diagnosed between ages 30 and 70. They come to medical attention due to new or worsening hypertension, often with hypokalemia. The precise role of KCNJ5 mutations in APA is under debate. They produce increased sodium conductance and cell depolarization, which in adrenal glomerulosa cells produces calcium entry, the signal for aldosterone production and cell proliferation. However, they may not be causative of APA development but may be a consequence of tumorigenesis, playing only a contributory role toward aldosterone overproduction and tumor growth. Somatic mutations in KCNJ5 have not been found in non-aldosterone secreting adrenal adenomas suggesting that they are specifically associated with APA. Mutations in KCNJ5 are involved in the pathogenesis of hypertension without primary aldosteronism but with increased aldosterone response to ACTH stimulation.

Activity regulation. Heteromultimer composed of KCNJ3/GIRK1 and KCNJ5/GIRK4 is activated by phosphatidylinositol 4,5 biphosphate (PtdIns(4,5)P2).

Similarity. Belongs to the inward rectifier-type potassium channel (TC 1.A.2.1) family. KCNJ5 subfamily.

RefSeq proteins (2): NP_000881, NP_001341098 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003277	K_chnl_inward-rec_Kir3.4	Family
IPR013518	K_chnl_inward-rec_Kir_cyto	Homologous_superfamily
IPR014756	Ig_E-set	Homologous_superfamily
IPR016449	K_chnl_inward-rec_Kir	Family
IPR040445	Kir_TM	Domain
IPR041647	IRK_C	Domain

Pfam: PF01007, PF17655

Catalyzed reactions (Rhea), 1 shown:

• K(+)(in) = K(+)(out) (RHEA:29463)

UniProt features (29 total): sequence variant 13, topological domain 4, transmembrane region 2, sequence conflict 2, intramembrane region 2, chain 1, short sequence motif 1, compositionally biased region 1, site 1, modified residue 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P48544-F1	82.01	0.67

Functional residue map

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

Catalytic / active sites (1): 179 (role in the control of polyamine-mediated channel gating and in the blocking by intracellular magnesium)

Post-translational modifications (1): 5

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-1296041	Activation of G protein gated Potassium channels
R-HSA-997272	Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits
R-HSA-112314	Neurotransmitter receptors and postsynaptic signal transmission
R-HSA-112315	Transmission across Chemical Synapses
R-HSA-112316	Neuronal System
R-HSA-1296059	G protein gated Potassium channels
R-HSA-1296065	Inwardly rectifying K+ channels
R-HSA-1296071	Potassium Channels
R-HSA-977443	GABA receptor activation
R-HSA-977444	GABA B receptor activation
R-HSA-991365	Activation of GABAB receptors

MSigDB gene sets: 352 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, FREAC2_01, MODULE_169, GOBP_CIRCULATORY_SYSTEM_PROCESS, REACTOME_POTASSIUM_CHANNELS, REACTOME_INWARDLY_RECTIFYING_K_CHANNELS, FOXO1_01, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_CELL_CELL_SIGNALING, GOBP_MUSCLE_CONTRACTION, FREAC3_01, GOBP_CELL_COMMUNICATION_INVOLVED_IN_CARDIAC_CONDUCTION, GOBP_REGULATION_OF_HEART_RATE, GOBP_CELL_CELL_SIGNALING_INVOLVED_IN_CARDIAC_CONDUCTION, GOBP_CARDIAC_MUSCLE_CELL_CONTRACTION

GO Biological Process (11): potassium ion transport (GO:0006813), regulation of monoatomic ion transmembrane transport (GO:0034765), potassium ion transmembrane transport (GO:0071805), regulation of heart rate by cardiac conduction (GO:0086091), membrane repolarization during atrial cardiac muscle cell action potential (GO:0098914), ventricular cardiac muscle cell membrane repolarization (GO:0099625), potassium ion import across plasma membrane (GO:1990573), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220), monoatomic cation transmembrane transport (GO:0098655), membrane repolarization during ventricular cardiac muscle cell action potential (GO:0098915)

GO Molecular Function (5): inward rectifier potassium channel activity (GO:0005242), G-protein activated inward rectifier potassium channel activity (GO:0015467), voltage-gated potassium channel activity involved in atrial cardiac muscle cell action potential repolarization (GO:0086089), voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization (GO:1902282), protein binding (GO:0005515)

GO Cellular Component (6): plasma membrane (GO:0005886), voltage-gated potassium channel complex (GO:0008076), I(KACh) inward rectifier potassium channel complex (GO:1990566), membrane (GO:0016020), monoatomic ion channel complex (GO:0034702), inward rectifier potassium channel complex (GO:1902937)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Neuronal System	2
G protein gated Potassium channels	1
Activation of GABAB receptors	1
Transmission across Chemical Synapses	1
Inwardly rectifying K+ channels	1
Potassium Channels	1
Neurotransmitter receptors and postsynaptic signal transmission	1
GABA receptor activation	1
GABA B receptor activation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
monoatomic ion transmembrane transport	2
membrane repolarization during cardiac muscle cell action potential	2
atrial cardiac muscle cell action potential	2
voltage-gated potassium channel activity involved in cardiac muscle cell action potential repolarization	2
metal ion transport	1
regulation of transmembrane transport	1
regulation of monoatomic ion transport	1
potassium ion transport	1
monoatomic cation transmembrane transport	1
regulation of heart rate	1
cardiac conduction	1
atrial cardiac muscle cell membrane repolarization	1
cardiac muscle cell membrane repolarization	1
potassium ion transmembrane transport	1
inorganic cation import across plasma membrane	1
transport	1
monoatomic ion transport	1
transmembrane transport	1
monoatomic cation transport	1
ventricular cardiac muscle cell action potential	1
ventricular cardiac muscle cell membrane repolarization	1
voltage-gated potassium channel activity	1
ligand-gated monoatomic cation channel activity	1
inward rectifier potassium channel activity	1
membrane repolarization during ventricular cardiac muscle cell action potential	1
binding	1
membrane	1
cell periphery	1
potassium channel complex	1
plasma membrane protein complex	1
inward rectifier potassium channel complex	1
cellular anatomical structure	1
transmembrane transporter complex	1
voltage-gated potassium channel complex	1

Protein interactions and networks

STRING

1102 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCNJ5	KCNJ3	P48549	984
KCNJ5	ATP2B3	Q16720	878
KCNJ5	KCNJ6	P48051	876
KCNJ5	KCNJ9	Q92806	865
KCNJ5	SCN4B	Q8IWT1	841
KCNJ5	CYP11B2	P19099	812
KCNJ5	KCNE2	Q9Y6J6	803
KCNJ5	ATP1A1	P05023	802
KCNJ5	ATP1A4	Q13733	799
KCNJ5	CACNA1D	Q01668	797
KCNJ5	KCNE1	P15382	796
KCNJ5	KCNH2	Q12809	789
KCNJ5	ATP1A3	P13637	785
KCNJ5	SNTA1	Q13424	770
KCNJ5	AKAP9	Q99996	758

IntAct

12 interactions, top by confidence:

A	B	Type	Score
PRIM1	POLA1	psi-mi:“MI:0914”(association)	0.640
KCNJ5	KCNJ15	psi-mi:“MI:0915”(physical association)	0.560
KCNJ5	KCNJ18	psi-mi:“MI:0915”(physical association)	0.400
KCNJ5	ADRB2	psi-mi:“MI:0915”(physical association)	0.370
KCNJ5	ERI3	psi-mi:“MI:0914”(association)	0.350
LONRF1	KCNJ5	psi-mi:“MI:0914”(association)	0.350
KCNJ5	KCNJ6	psi-mi:“MI:0914”(association)	0.350
KCNJ5	KCNJ15	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (33): KCNJ3 (Affinity Capture-MS), ERI3 (Affinity Capture-MS), WDR45B (Affinity Capture-MS), LANCL2 (Affinity Capture-MS), MTMR6 (Affinity Capture-MS), GNB2 (Affinity Capture-MS), PLCG1 (Affinity Capture-MS), ATG7 (Affinity Capture-MS), GNB1L (Affinity Capture-MS), PKP4 (Affinity Capture-MS), KCNJ5 (Affinity Capture-MS), NUP35 (Affinity Capture-MS), GNB4 (Affinity Capture-MS), KCNJ15 (Two-hybrid), KCNJ5 (Reconstituted Complex)

ESM2 similar proteins: B7U540, E1BNE9, F1MYR9, F1NHE9, O02670, O02822, O18839, O19182, O70617, P35561, P48050, P48051, P48542, P48543, P48544, P48545, P48548, P48549, P48550, P49656, P49658, P52185, P52186, P52187, P52188, P52189, P52190, P52191, P52192, P63250, P63251, P63252, P63253, P70673, P97794, Q14500, Q14654, Q15842, Q4TZY1, Q5NVJ6

Diamond homologs: B7U540, E1BN00, E1BNE9, F1MYR9, F1NHE9, O02670, O02822, O18839, O19182, O60928, O70339, O70596, O70617, O88335, O88932, P35560, P35561, P48048, P48050, P48051, P48542, P48543, P48544, P48545, P48548, P48549, P48550, P49655, P49656, P49658, P52185, P52186, P52187, P52188, P52189, P52190, P52191, P52192, P63250, P63251

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
KCNJ5	“form complex”	KCNJ5/KCNJ3	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	3
Uncertain significance	274
Likely benign	149
Benign	38

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
135679	NM_000890.5(KCNJ5):c.452G>A (p.Gly151Glu)	Pathogenic
135680	NM_000890.5(KCNJ5):c.470T>G (p.Ile157Ser)	Pathogenic
135681	NM_000890.5(KCNJ5):c.736G>A (p.Glu246Lys)	Pathogenic
30125	NM_000890.5(KCNJ5):c.472A>G (p.Thr158Ala)	Pathogenic
91915	NM_000890.5(KCNJ5):c.451G>A (p.Gly151Arg)	Pathogenic
1467663	NM_000890.5(KCNJ5):c.473C>G (p.Thr158Arg)	Likely pathogenic
91916	NM_000890.5(KCNJ5):c.451G>C (p.Gly151Arg)	Likely pathogenic
91917	NM_000890.5(KCNJ5):c.503T>G (p.Leu168Arg)	Likely pathogenic

SpliceAI

1221 predictions. Top by Δscore:

Variant	Effect	Δscore
11:128905555:C:A	donor_gain	1.0000
11:128916581:G:GT	donor_gain	1.0000
11:128916588:G:GT	donor_gain	1.0000
11:128916588:G:T	donor_gain	1.0000
11:128916605:G:GG	donor_gain	1.0000
11:128916682:A:G	donor_gain	1.0000
11:128904427:TTAC:T	donor_loss	0.9900
11:128904428:TACC:T	donor_loss	0.9900
11:128904429:ACCT:A	donor_loss	0.9900
11:128904430:CCTGT:C	donor_loss	0.9900
11:128905293:T:TA	donor_gain	0.9900
11:128905550:T:TA	donor_gain	0.9900
11:128911262:A:AG	acceptor_gain	0.9900
11:128911263:G:GG	acceptor_gain	0.9900
11:128911263:GC:G	acceptor_gain	0.9900
11:128912162:G:GT	donor_gain	0.9900
11:128912206:CACAG:C	donor_loss	0.9900
11:128912207:ACAGG:A	donor_loss	0.9900
11:128912208:CAGG:C	donor_loss	0.9900
11:128912211:G:T	donor_loss	0.9900
11:128912212:T:A	donor_loss	0.9900
11:128916589:A:T	donor_gain	0.9900
11:128916663:GC:G	donor_gain	0.9900
11:128891719:CAAGT:C	donor_loss	0.9800
11:128891720:AAG:A	donor_loss	0.9800
11:128891721:AGT:A	donor_loss	0.9800
11:128891722:G:C	donor_loss	0.9800
11:128891722:G:GG	donor_gain	0.9800
11:128891723:T:A	donor_loss	0.9800
11:128905296:T:TA	donor_gain	0.9800

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000059984 (11:128894430 T>G), RS1000334316 (11:128909490 G>A,T), RS1000374345 (11:128894275 G>A), RS1000445472 (11:128916778 C>T), RS1000640881 (11:128915311 C>T), RS1000672853 (11:128910895 A>G), RS1000782013 (11:128918166 C>A), RS1000850558 (11:128905248 C>G,T), RS1000957433 (11:128899949 G>A,T), RS1001204021 (11:128919370 GGA>G), RS1001301659 (11:128906193 A>G), RS1001317905 (11:128912978 G>C), RS1001424898 (11:128906911 AT>A), RS1001551709 (11:128889542 C>A,G), RS1001650546 (11:128895540 C>T)

Disease associations

OMIM: gene MIM:600734 | disease phenotypes: MIM:613485, MIM:613677, MIM:170390

GenCC curated gene-disease

Disease	Classification	Inheritance
familial hyperaldosteronism type III	Definitive	Autosomal dominant
Andersen-Tawil syndrome	Supportive	Autosomal dominant
long QT syndrome 13	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
familial hyperaldosteronism type III	Definitive	AD
long QT syndrome	Disputed	AD

Mondo (6): long QT syndrome (MONDO:0002442), long QT syndrome 13 (MONDO:0013279), familial hyperaldosteronism type III (MONDO:0013359), dilated cardiomyopathy (MONDO:0005021), Andersen-Tawil syndrome (MONDO:0008222), hypertrophic cardiomyopathy (MONDO:0005045)

Orphanet (6): Romano-Ward syndrome (Orphanet:101016), Familial hyperaldosteronism type III (Orphanet:251274), Congenital long QT syndrome (Orphanet:768), Dilated cardiomyopathy (Orphanet:217604), Andersen-Tawil syndrome (Orphanet:37553), Rare hypertrophic cardiomyopathy (Orphanet:217569)

HPO phenotypes

93 total (30 of 93 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000089	Renal hypoplasia
HP:0000103	Polyuria
HP:0000124	Renal tubular dysfunction
HP:0000164	Abnormality of the dentition
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000316	Hypertelorism
HP:0000324	Facial asymmetry
HP:0000325	Triangular face
HP:0000327	Hypoplasia of the maxilla
HP:0000337	Broad forehead
HP:0000347	Micrognathia
HP:0000360	Tinnitus
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000414	Bulbous nose
HP:0000421	Epistaxis
HP:0000431	Wide nasal bridge
HP:0000677	Oligodontia
HP:0000678	Dental crowding
HP:0000822	Hypertension
HP:0000859	Increased circulating aldosterone concentration
HP:0001197	Abnormality of prenatal development or birth
HP:0001250	Seizure
HP:0001279	Syncope
HP:0001324	Muscle weakness
HP:0001328	Specific learning disability
HP:0001382	Joint hypermobility
HP:0001510	Growth delay

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST003818_82	Resting heart rate	1.000000e-16
GCST004297_8	Atrial fibrillation	3.000000e-08
GCST006061_70	Atrial fibrillation	2.000000e-20
GCST006061_71	Atrial fibrillation	9.000000e-21
GCST006291_13	Spherical equivalent or myopia (age of diagnosis)	3.000000e-08
GCST006414_7	Atrial fibrillation	1.000000e-20
GCST010002_202	Refractive error	1.000000e-17
GCST010796_3701	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-08
GCST010796_3702	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-09
GCST010796_3816	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-08
GCST010796_3817	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST010796_3818	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-09
GCST010796_3819	Electrocardiogram morphology (amplitude at temporal datapoints)	9.000000e-09
GCST010796_3820	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-08
GCST010796_3821	Electrocardiogram morphology (amplitude at temporal datapoints)	9.000000e-09
GCST010796_3822	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-08
GCST010796_3823	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST010796_3824	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_3825	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004847	age at onset
EFO:0004327	electrocardiography

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D050030	Andersen Syndrome	C14.280.067.565.070; C14.280.123.625.070; C16.131.240.400.715.070; C23.550.073.547.070
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1914278 (SINGLE PROTEIN), CHEMBL3038488 (PROTEIN COMPLEX)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: vgic — Inwardly rectifying potassium channels (K_IR)

Most potent curated ligand interactions (11 total), top 11:

Ligand	Action	Affinity	Parameter
tertiapin-Q	Antagonist	7.9	pIC50
AZD2927	Channel blocker	5.9	pIC50
imipramine	Antagonist	4.5	pEC50
desipramine	Antagonist	4.3	pIC50
Cs+	Antagonist	4.0	pEC50
amitriptyline	Antagonist	3.6	pIC50
clomipramine	Antagonist	3.6	pIC50
maprotiline	Antagonist	3.5	pIC50
nortriptyline	Antagonist	3.4	pIC50
Ba2+	Antagonist	3.3	pEC50
Na+	Agonist	1.4	pEC50

Binding affinities (BindingDB)

38 measured of 38 human assays (38 total across all organisms); most potent 38 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
3-(4-(isopropylamino)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine-7-carbonitrile	IC50	2 nM	US-10202390: Heteroaryl substituted aminopyridine compounds
3-[5-[1-(1-acetylazetidin-3-yl)triazol-4-yl]-4-(propan-2-ylamino)-2-pyridinyl]imidazo[1,2-b]pyridazine-7-carbonitrile	IC50	2 nM	US-10202390: Heteroaryl substituted aminopyridine compounds
3-[4-(cyclopropylamino)-5-(1-propyltriazol-4-yl)-2-pyridinyl]imidazo[1,2-b]pyridazine-7-carbonitrile	IC50	2 nM	US-10202390: Heteroaryl substituted aminopyridine compounds
3-[5-[5-(3-hydroxy-3-methylbutyl)-1H-pyrazol-3-yl]-4-(oxan-4-ylamino)-2-pyridinyl]pyrazolo[1,5-a]pyrimidine-6-carbonitrile	IC50	2 nM	US-10202390: Heteroaryl substituted aminopyridine compounds
4-[1-[6-(6-chloropyrazolo[1,5-a]pyrimidin-3-yl)-4-(propan-2-ylamino)-3-pyridinyl]triazol-4-yl]-2-methylbutan-2-ol	IC50	3 nM	US-10202390: Heteroaryl substituted aminopyridine compounds
2-(7-chloroimidazo[1,2-b]pyridazin-3-yl)-N-cyclopropyl-5-(1-propyltriazol-4-yl)pyridin-4-amine	IC50	3 nM	US-10202390: Heteroaryl substituted aminopyridine compounds
3-(5-(1-(3-hydroxy-3-methylbutyl)-1H-pyrazol-4-yl)-4-(isopropylamino)pyridin-2-yl) imidazo[1,2-b]pyridazine-7-carbonitrile	IC50	3 nM	US-10202390: Heteroaryl substituted aminopyridine compounds
3-[5-[4-(3-hydroxy-3-methylbutyl)triazol-1-yl]-4-(propan-2-ylamino)-2-pyridinyl]imidazo[1,2-b]pyridazine-7-carbonitrile	IC50	4 nM	US-10202390: Heteroaryl substituted aminopyridine compounds
3-[4-[[(1S,3S)-3-fluorocyclopentyl]amino]-5-[4-(3-hydroxy-3-methylbutyl)triazol-1-yl]-2-pyridinyl]pyrazolo[1,5-a]pyrimidine-6-carbonitrile	IC50	5 nM	US-10202390: Heteroaryl substituted aminopyridine compounds
3-[5-[5-(oxan-4-yl)-1H-pyrazol-3-yl]-4-(propan-2-ylamino)-2-pyridinyl]imidazo[1,2-b]pyridazine-7-carbonitrile	IC50	5 nM	US-10202390: Heteroaryl substituted aminopyridine compounds
3-(4-(isopropylamino)-5-(4-propyl-1H-1,2,3-triazol-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine-7-carbonitrile	IC50	6 nM	US-10202390: Heteroaryl substituted aminopyridine compounds
2-(6-chloropyrazolo[1,5-a]pyrimidin-3-yl)-N-isopropyl-5-(4-propyl-1H-1,2,3-triazol-1-yl)pyridin-4-amine	IC50	8 nM	US-10202390: Heteroaryl substituted aminopyridine compounds
3-[4-(propan-2-ylamino)-5-(4-propyltriazol-1-yl)-2-pyridinyl]pyrazolo[1,5-a]pyrimidine-6-carbonitrile	IC50	9 nM	US-10202390: Heteroaryl substituted aminopyridine compounds
4-[1-[6-(6-chloropyrazolo[1,5-a]pyrimidin-3-yl)-4-(oxetan-3-ylamino)-3-pyridinyl]triazol-4-yl]-2-methylbutan-2-ol	IC50	9 nM	US-10202390: Heteroaryl substituted aminopyridine compounds
4-[1-[6-(6-chloropyrazolo[1,5-a]pyrimidin-3-yl)-4-(oxan-4-ylamino)-3-pyridinyl]triazol-4-yl]-2-methylbutan-2-ol	IC50	9 nM	US-10202390: Heteroaryl substituted aminopyridine compounds
3-[5-[4-(3-hydroxy-3-methylbutyl)triazol-1-yl]-4-(oxetan-3-ylamino)-2-pyridinyl]pyrazolo[1,5-a]pyrimidine-6-carbonitrile	IC50	10 nM	US-10202390: Heteroaryl substituted aminopyridine compounds
2-(7-chloroimidazo[1,2-b]pyridazin-3-yl)-N-propan-2-yl-5-(1-propyltriazol-4-yl)pyridin-4-amine	IC50	12 nM	US-10202390: Heteroaryl substituted aminopyridine compounds
3-[5-[1-(oxan-4-yl)pyrazol-4-yl]-4-(propan-2-ylamino)-2-pyridinyl]imidazo[1,2-b]pyridazine-7-carbonitrile	IC50	14 nM	US-10202390: Heteroaryl substituted aminopyridine compounds
methyl (3R)-4-[4-[6-(7-chloroimidazo[1,2-b]pyridazin-3-yl)-4-(cyclopropylamino)-3-pyridinyl]triazol-1-yl]-3-hydroxy-3-methylpiperidine-1-carboxylate	IC50	14 nM	US-10202390: Heteroaryl substituted aminopyridine compounds
3-[4-[(3,3-difluorocyclobutyl)amino]-5-[4-(3-hydroxy-3-methylbutyl)triazol-1-yl]-2-pyridinyl]pyrazolo[1,5-a]pyrimidine-6-carbonitrile	IC50	14 nM	US-10202390: Heteroaryl substituted aminopyridine compounds
3-[4-(propan-2-ylamino)-5-(1-propylpyrazol-4-yl)-2-pyridinyl]imidazo[1,2-b]pyridazine-7-carbonitrile	IC50	18 nM	US-10202390: Heteroaryl substituted aminopyridine compounds
3-[4-[[1-(2,2-difluoroethyl)pyrazol-4-yl]amino]-5-(1-propylpyrazol-4-yl)-2-pyridinyl]imidazo[1,2-b]pyridazine-7-carbonitrile	IC50	20 nM	US-10202390: Heteroaryl substituted aminopyridine compounds
2-(7-chloroimidazo[1,2-b]pyridazin-3-yl)-N-[1-(2,2-difluoroethyl)pyrazol-4-yl]-5-(1-propylpyrazol-4-yl)pyridin-4-amine	IC50	29 nM	US-10202390: Heteroaryl substituted aminopyridine compounds
US12084442, Example 18	IC50	30 nM	US-12084442: Naphthyridinone derivatives for the treatment of a disease or disorder
3-[4-(propan-2-ylamino)-5-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-2-pyridinyl]imidazo[1,2-b]pyridazine-7-carbonitrile	IC50	43 nM	US-10202390: Heteroaryl substituted aminopyridine compounds
US12084442, Example 19	IC50	50 nM	US-12084442: Naphthyridinone derivatives for the treatment of a disease or disorder
US12084442, Example 5	IC50	60 nM	US-12084442: Naphthyridinone derivatives for the treatment of a disease or disorder
US12084442, Example 13	IC50	60 nM	US-12084442: Naphthyridinone derivatives for the treatment of a disease or disorder
2-(7-chloroimidazo[1,2-b]pyridazin-3-yl)-N-isopropyl-5-(4-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-1-yl)pyridin-4-amine	IC50	63 nM	US-10202390: Heteroaryl substituted aminopyridine compounds
US12084442, Example 8	IC50	70 nM	US-12084442: Naphthyridinone derivatives for the treatment of a disease or disorder
US12084442, Example 6	IC50	130 nM	US-12084442: Naphthyridinone derivatives for the treatment of a disease or disorder
US12084442, Example 4	IC50	160 nM	US-12084442: Naphthyridinone derivatives for the treatment of a disease or disorder
US12084442, Example 14	IC50	170 nM	US-12084442: Naphthyridinone derivatives for the treatment of a disease or disorder
3-[5-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-4-(propan-2-ylamino)-2-pyridinyl]imidazo[1,2-b]pyridazine-7-carbonitrile	IC50	174 nM	US-10202390: Heteroaryl substituted aminopyridine compounds
US12084442, Example 12	IC50	200 nM	US-12084442: Naphthyridinone derivatives for the treatment of a disease or disorder
US12084442, Example 15	IC50	320 nM	US-12084442: Naphthyridinone derivatives for the treatment of a disease or disorder
1-[4-[6-(7-chloroimidazo[1,2-b]pyridazin-3-yl)-4-(propan-2-ylamino)-3-pyridinyl]pyrazol-1-yl]-2-methylpropan-2-ol	IC50	396 nM	US-10202390: Heteroaryl substituted aminopyridine compounds
3-(5-(4-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-4-(isopropylamino)pyridin-2-yl) pyrazolo[1,5-a]pyrimidine-6-carbonitrile	IC50	578 nM	US-10202390: Heteroaryl substituted aminopyridine compounds

ChEMBL bioactivities

341 potent at pChembl≥5 of 350 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.70	IC50	2	nM	CHEMBL5281961
8.70	IC50	2	nM	CHEMBL5804730
8.70	IC50	2	nM	CHEMBL6045550
8.70	IC50	2	nM	CHEMBL5751984
8.70	IC50	2	nM	CHEMBL5982340
8.52	IC50	3	nM	CHEMBL5841402
8.52	IC50	3	nM	CHEMBL6025760
8.52	IC50	3	nM	CHEMBL5757725
8.40	IC50	4	nM	CHEMBL6058410
8.30	IC50	5	nM	CHEMBL5921371
8.30	IC50	5	nM	CHEMBL5756136
8.22	IC50	6	nM	CHEMBL5798851
8.22	IC50	6	nM	CHEMBL5991011
8.10	IC50	8	nM	CHEMBL5856774
8.10	IC50	8	nM	CHEMBL6049828
8.09	Ki	8.2	nM	CHEMBL4559408
8.05	IC50	9	nM	CHEMBL5287217
8.05	IC50	9	nM	CHEMBL5953582
8.05	IC50	9	nM	CHEMBL6028623
8.05	IC50	9	nM	CHEMBL5815068
8.05	IC50	9	nM	CHEMBL5856252
8.00	IC50	10	nM	CHEMBL5982721
7.96	IC50	11	nM	CHEMBL5280047
7.96	IC50	11	nM	CHEMBL5933498
7.92	IC50	12	nM	CHEMBL5872178
7.89	IC50	13	nM	CHEMBL5964704
7.89	IC50	13	nM	CHEMBL5904969
7.85	IC50	14	nM	CHEMBL5943053
7.85	IC50	14	nM	CHEMBL6044301
7.85	IC50	14	nM	CHEMBL6030012
7.85	IC50	14	nM	CHEMBL5902009
7.82	IC50	15	nM	CHEMBL5926185
7.82	IC50	15	nM	CHEMBL5815902
7.80	IC50	16	nM	CHEMBL6054985
7.77	IC50	17	nM	CHEMBL5914041
7.75	IC50	18	nM	CHEMBL6003213
7.72	IC50	19	nM	CHEMBL5923594
7.70	IC50	20	nM	CHEMBL5745314
7.64	IC50	23	nM	CHEMBL5871373
7.62	IC50	24	nM	CHEMBL5884668
7.60	IC50	25	nM	CHEMBL5271366
7.60	IC50	25	nM	CHEMBL6027311
7.58	IC50	26	nM	CHEMBL5819126
7.57	IC50	27	nM	CHEMBL5289977
7.55	IC50	28	nM	CHEMBL5885722
7.55	IC50	28	nM	CHEMBL6035325
7.54	IC50	29	nM	CHEMBL5776964
7.54	IC50	29	nM	CHEMBL5915351
7.51	IC50	31	nM	CHEMBL5838250
7.50	IC50	32	nM	CHEMBL5931550

PubChem BioAssay actives

185 with measured affinity, of 686 total; 50 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
1-(2,6-dichloro-4-methoxyphenyl)-5-fluoro-2-methyl-1,7-naphthyridin-4-one	1951993: Inhibition of recombinant human GIRK1/4 channel	ic50	0.0020	uM
(1R,4S,7S,10S,16S,19S,22S,25R,28S,31R,36R,39S,42S,45S,52R,55S)-39,42-bis(4-aminobutyl)-N-[2-[[(2S)-6-amino-1-[[(2S)-1,6-diamino-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-2-oxoethyl]-28,55-bis(2-amino-2-oxoethyl)-52-[[(2S)-2-[[(2S)-2-aminopropanoyl]amino]-4-methylpentanoyl]amino]-16,19,22-tris[(2S)-butan-2-yl]-25-(3-carbamimidamidopropyl)-7-(1H-imidazol-5-ylmethyl)-45-(1H-indol-3-ylmethyl)-4-(2-methylsulfanylethyl)-3,6,9,15,18,21,24,27,30,38,41,44,47,53,56-pentadecaoxo-33,34,49,50-tetrathia-2,5,8,14,17,20,23,26,29,37,40,43,46,54,57-pentadecazatricyclo[29.16.10.010,14]heptapentacontane-36-carboxamide	1525458: Inhibition GIRK1/4 (unknown origin)	ki	0.0082	uM
8-chloro-1-(2,6-dichlorophenyl)-5-(2-hydroxyethoxy)-2-methyl-1,6-naphthyridin-4-one	1951993: Inhibition of recombinant human GIRK1/4 channel	ic50	0.0090	uM
1-[2,6-dichloro-4-(2,3-dihydroxypropoxy)phenyl]-5-fluoro-2-methyl-1,7-naphthyridin-4-one	1951993: Inhibition of recombinant human GIRK1/4 channel	ic50	0.0110	uM
8-chloro-1-(2,6-dichlorophenyl)-5-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]-2-methyl-1,6-naphthyridin-4-one	1951993: Inhibition of recombinant human GIRK1/4 channel	ic50	0.0250	uM
8-chloro-1-(2,6-dichlorophenyl)-2-(hydroxymethyl)-5-methoxy-1,6-naphthyridin-4-one	1951993: Inhibition of recombinant human GIRK1/4 channel	ic50	0.0270	uM
1-(2,6-dichlorophenyl)-7-fluoro-2-methylsulfanyl-4-oxoquinoline-3-carbonitrile	1951993: Inhibition of recombinant human GIRK1/4 channel	ic50	0.0500	uM
8-chloro-1-(2,6-dichlorophenyl)-5-(2,3-dihydroxypropoxy)-2-(hydroxymethyl)-1,6-naphthyridin-4-one	1951993: Inhibition of recombinant human GIRK1/4 channel	ic50	0.0800	uM
8-chloro-1-(2,6-dichlorophenyl)-2-methyl-5-(2,4,5-trihydroxypentoxy)-1,6-naphthyridin-4-one	1951993: Inhibition of recombinant human GIRK1/4 channel	ic50	0.0870	uM
8-chloro-1-(2,6-dichlorophenyl)-5-[(2R)-2,3-dihydroxypropoxy]-2-(hydroxymethyl)-1,6-naphthyridin-4-one	1951993: Inhibition of recombinant human GIRK1/4 channel	ic50	0.1000	uM
8-chloro-1-(2,6-dichlorophenyl)-2-(hydroxymethyl)-5-(3-methylsulfonylpropoxy)-1,6-naphthyridin-4-one	1951993: Inhibition of recombinant human GIRK1/4 channel	ic50	0.1000	uM
1-(2-benzyl-5-methylpyrazol-3-yl)-3-(3,4-difluorophenyl)urea	762447: Activation of GIRK1/4 (unknown origin)	ec50	0.1100	uM
1-[2,6-dichloro-4-(3-hydroxyprop-1-ynyl)phenyl]-5-fluoro-2-methyl-1,7-naphthyridin-4-one	1951993: Inhibition of recombinant human GIRK1/4 channel	ic50	0.1400	uM
2-(2,4-dichlorophenoxy)-N-[2-(4,4-difluorocyclohexyl)-5-methylpyrazol-3-yl]acetamide	1865721: Activation of GIRK1/4 channel (unknown origin) expressed in HEK293 cells incubated for 6 mins by thallium flux assay	ec50	0.1450	uM
8-chloro-1-(2,6-dichlorophenyl)-5-[(2S)-2,3-dihydroxypropoxy]-2-(hydroxymethyl)-1,6-naphthyridin-4-one	1951993: Inhibition of recombinant human GIRK1/4 channel	ic50	0.1500	uM
8-chloro-1-(2,6-dichlorophenyl)-5-[3-(2,3-dihydroxypropoxy)-2-hydroxypropoxy]-2-methyl-1,6-naphthyridin-4-one	1951993: Inhibition of recombinant human GIRK1/4 channel	ic50	0.1700	uM
1-[3-(cyclopropylmethyl)-1-phenylpyrazol-5-yl]-3-(3-fluorophenyl)urea	762440: Inhibition of GIRK1/4 (unknown origin)	ic50	0.1800	uM
3,5-dichloro-4-(5-fluoro-2-methyl-4-oxo-1,7-naphthyridin-1-yl)benzonitrile	1951993: Inhibition of recombinant human GIRK1/4 channel	ic50	0.1900	uM
1-[3-(2,2-difluorocyclopropyl)-1-phenylpyrazol-5-yl]-3-(4-fluoro-3-methylphenyl)urea	1166632: Inhibition of GIRK1/4 (unknown origin) by thallium-flux based assay	ic50	0.2000	uM
1-[2,6-dichloro-4-(3-morpholin-4-ylprop-1-ynyl)phenyl]-5-fluoro-2-methyl-1,7-naphthyridin-4-one	1951993: Inhibition of recombinant human GIRK1/4 channel	ic50	0.2200	uM
2-(2,4-dibromophenoxy)-N-[2-(1,1-dioxothiolan-3-yl)-5-methylpyrazol-3-yl]acetamide	1865721: Activation of GIRK1/4 channel (unknown origin) expressed in HEK293 cells incubated for 6 mins by thallium flux assay	ec50	0.2290	uM
2-(2-chlorophenyl)-N-[4-chloro-3-(trifluoromethyl)phenyl]acetamide	766856: Activation of GIRK1/4 (unknown origin) transfected in HEK293 cells after 4 mins by thallium flux-based fluorescence assay	ec50	0.2400	uM
8-chloro-1-(2,6-dichlorophenyl)-5-(1,3-dihydroxypropan-2-yloxy)-2-(hydroxymethyl)-1,6-naphthyridin-4-one	1951993: Inhibition of recombinant human GIRK1/4 channel	ic50	0.2500	uM
1-[3-(cyclopropylmethyl)-1-phenylpyrazol-5-yl]-3-(3-methylphenyl)urea	762440: Inhibition of GIRK1/4 (unknown origin)	ic50	0.2500	uM
1-[3-(cyclopropylmethyl)-1-phenylpyrazol-5-yl]-3-[3-(trifluoromethyl)phenyl]urea	762440: Inhibition of GIRK1/4 (unknown origin)	ic50	0.2500	uM
N-(2-cyclohexyl-5-methylpyrazol-3-yl)-2-(5-phenyltetrazol-2-yl)acetamide	1624838: Activation of human GIRK1/4 expressed in HEK293 cells co-expressing rat mGlu8 by thallium flux assay	ec50	0.2590	uM
N-(2-cyclohexyl-5-methylpyrazol-3-yl)-2-[5-(3-fluorophenyl)tetrazol-2-yl]acetamide	1624838: Activation of human GIRK1/4 expressed in HEK293 cells co-expressing rat mGlu8 by thallium flux assay	ec50	0.2640	uM
1-[3-(cyclopropylmethyl)-1-phenylpyrazol-5-yl]-3-(4-fluorophenyl)urea	762440: Inhibition of GIRK1/4 (unknown origin)	ic50	0.2700	uM
N-[2-(cyclohexylmethyl)-5-methylpyrazol-3-yl]-2-(5-phenyltetrazol-2-yl)acetamide	1624838: Activation of human GIRK1/4 expressed in HEK293 cells co-expressing rat mGlu8 by thallium flux assay	ec50	0.2830	uM
1-(2,6-dichlorophenyl)-2-(hydroxymethyl)-5-methoxy-8-methyl-1,6-naphthyridin-4-one	1951993: Inhibition of recombinant human GIRK1/4 channel	ic50	0.2900	uM
N-(2-cyclohexyl-5-methylpyrazol-3-yl)-2-[5-(3-methoxyphenyl)tetrazol-2-yl]acetamide	1624838: Activation of human GIRK1/4 expressed in HEK293 cells co-expressing rat mGlu8 by thallium flux assay	ec50	0.2990	uM
1-(3-chloro-4-fluorophenyl)-3-[3-(cyclopropylmethyl)-1-phenylpyrazol-5-yl]urea	762440: Inhibition of GIRK1/4 (unknown origin)	ic50	0.3100	uM
1-(1-benzyl-3-cyclopropylpyrazol-5-yl)-3-(3-chloro-4-fluorophenyl)urea	762447: Activation of GIRK1/4 (unknown origin)	ec50	0.3200	uM
2-(4-bromo-2-chlorophenoxy)-N-[2-(1,1-dioxothiolan-3-yl)-5-methylpyrazol-3-yl]acetamide	1865721: Activation of GIRK1/4 channel (unknown origin) expressed in HEK293 cells incubated for 6 mins by thallium flux assay	ec50	0.3350	uM
1-(3-chlorophenyl)-3-[3-(cyclopropylmethyl)-1-phenylpyrazol-5-yl]urea	762440: Inhibition of GIRK1/4 (unknown origin)	ic50	0.3400	uM
N-(2-cyclohexyl-5-methylpyrazol-3-yl)-2-(4-phenylpyrazol-1-yl)acetamide	1624838: Activation of human GIRK1/4 expressed in HEK293 cells co-expressing rat mGlu8 by thallium flux assay	ec50	0.3480	uM
2-(2,4-dichlorophenoxy)-N-[1-(1,1-dioxothiolan-3-yl)-3-ethylpyrazol-5-yl]acetamide	1865721: Activation of GIRK1/4 channel (unknown origin) expressed in HEK293 cells incubated for 6 mins by thallium flux assay	ec50	0.3600	uM
2-(2,4-dichlorophenoxy)-N-[5-methyl-2-(oxan-4-yl)pyrazol-3-yl]acetamide	1865721: Activation of GIRK1/4 channel (unknown origin) expressed in HEK293 cells incubated for 6 mins by thallium flux assay	ec50	0.3710	uM
N-[2-(4,4-difluorocyclohexyl)-5-methylpyrazol-3-yl]-2-(5-phenyltetrazol-2-yl)acetamide	1624838: Activation of human GIRK1/4 expressed in HEK293 cells co-expressing rat mGlu8 by thallium flux assay	ec50	0.3830	uM
N-(2-cyclohexyl-5-methylpyrazol-3-yl)-2-[5-(3,4-difluorophenyl)tetrazol-2-yl]acetamide	1624838: Activation of human GIRK1/4 expressed in HEK293 cells co-expressing rat mGlu8 by thallium flux assay	ec50	0.3920	uM
N-(2-cyclohexyl-5-methylpyrazol-3-yl)-2-[5-(4-methylphenyl)tetrazol-2-yl]acetamide	1624838: Activation of human GIRK1/4 expressed in HEK293 cells co-expressing rat mGlu8 by thallium flux assay	ec50	0.4080	uM
N-(2-cyclohexyl-5-methylpyrazol-3-yl)-2-(4-phenyltriazol-1-yl)acetamide	1624838: Activation of human GIRK1/4 expressed in HEK293 cells co-expressing rat mGlu8 by thallium flux assay	ec50	0.4120	uM
N-(2-cyclohexyl-5-methylpyrazol-3-yl)-2-(2,4-dichlorophenoxy)acetamide	1865721: Activation of GIRK1/4 channel (unknown origin) expressed in HEK293 cells incubated for 6 mins by thallium flux assay	ec50	0.4300	uM
N-(2-cyclohexyl-5-methylpyrazol-3-yl)-2-[5-(3-methylphenyl)tetrazol-2-yl]acetamide	1624838: Activation of human GIRK1/4 expressed in HEK293 cells co-expressing rat mGlu8 by thallium flux assay	ec50	0.4350	uM
N-(2-cyclohexyl-5-methylpyrazol-3-yl)-2-[5-(2-fluorophenyl)tetrazol-2-yl]acetamide	1624838: Activation of human GIRK1/4 expressed in HEK293 cells co-expressing rat mGlu8 by thallium flux assay	ec50	0.4470	uM
N-(2-cyclohexyl-5-methylpyrazol-3-yl)-2-[5-[4-(trifluoromethyl)phenyl]tetrazol-2-yl]acetamide	1624838: Activation of human GIRK1/4 expressed in HEK293 cells co-expressing rat mGlu8 by thallium flux assay	ec50	0.4480	uM
1-(3-chlorophenyl)-3-(3-cyclobutyl-1-phenylpyrazol-5-yl)urea	762440: Inhibition of GIRK1/4 (unknown origin)	ic50	0.4800	uM
1-(3,4-difluorophenyl)-3-[2-(4-fluorophenyl)-5-methylpyrazol-3-yl]urea	762447: Activation of GIRK1/4 (unknown origin)	ec50	0.5400	uM
1-[3-(1-methylcyclopropyl)-1-phenylpyrazol-5-yl]-3-(3-methylphenyl)urea	1166632: Inhibition of GIRK1/4 (unknown origin) by thallium-flux based assay	ic50	0.5500	uM
1-[3-(cyclopropylmethyl)-1-phenylpyrazol-5-yl]-3-(3,4-difluorophenyl)urea	762440: Inhibition of GIRK1/4 (unknown origin)	ic50	0.5600	uM

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects cotreatment, decreases expression, increases expression	2
Formaldehyde	increases expression	2
Genistein	increases expression	2
bisphenol A	increases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	decreases expression	1
avobenzone	decreases expression	1
CGP 52608	affects binding, increases reaction	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
(+)-JQ1 compound	decreases expression	1
Calcimycin	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Aldosterone	decreases reaction, increases secretion, decreases secretion	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cadmium	decreases expression	1
Dexamethasone	affects expression	1
Diethylstilbestrol	increases expression	1
Doxorubicin	decreases expression	1
Plant Extracts	decreases expression, affects cotreatment	1
Tetrachlorodibenzodioxin	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Triclosan	decreases expression	1
Valproic Acid	increases methylation	1
Vitamin E	decreases expression	1
Zearalenone	increases expression	1
1-Methyl-4-phenylpyridinium	increases expression	1
Aflatoxin B1	increases methylation	1

ChEMBL screening assays

32 unique, capped per target: 32 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4392958	Binding	Inhibition of Kir3.4 (unknown origin)	Potassium channel blocking 1,2-bis(aryl)ethane-1,2-diamines active as antiarrhythmic agents. — Bioorg Med Chem Lett

Cellosaurus cell lines

2 cell lines: 2 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_D0N9	UKMi005-A	Induced pluripotent stem cell	Female
CVCL_D1GB	UKMi006-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT00374465	PHASE4	UNKNOWN	Therapy With Verapamil or Carvedilol in Chronic Heart Failure
NCT01293903	PHASE4	COMPLETED	Study of Qiliqiangxin Capsule to Treat Dilated Cardiomyopathy
NCT01557140	PHASE4	COMPLETED	A Randomized Trial of Carvedilol in Chronic Chagas Cardiomyopathy
NCT01917149	PHASE4	COMPLETED	Supramaximal Titrated Inhibition of RAAS in Dilated Cardiomyopathy
NCT02115581	PHASE4	COMPLETED	Coenzyme Q10 Supplementation in Children With Idiopathic Dilated Cardiomyopathy
NCT06236022	PHASE4	RECRUITING	The Effects of Sirolimus in Patients With Dilated Cardiomyopathy Infected With Kaposi Sarcoma-associated Virus
NCT00879060	PHASE4	COMPLETED	Clinical and Therapeutic Implications of Fibrosis in Hypertrophic Cardiomyopathy
NCT01721967	PHASE4	COMPLETED	Ranolazine for the Treatment of Chest Pain in HCM Patients
NCT02948998	PHASE4	UNKNOWN	Evaluating the Effect of Spironolactone on Hypertrophic Cardiomyopathy
NCT03249272	PHASE4	TERMINATED	Microvascular Dysfunction in Nonischemic Cardiomyopathy: Insights From CMR Assessment of Coronary Flow Reserve
NCT04133532	PHASE4	COMPLETED	Effect of Metoprolol in Post Alcohol Septal Ablation Patients With Hypertrophic Cardiomyopathy
NCT06401343	PHASE4	RECRUITING	Use of SGLT2i in noHCM With HFpEF
NCT00333827	PHASE3	COMPLETED	Cell Therapy In Dilated Cardiomyopathy
NCT00505154	PHASE3	COMPLETED	Effect of Rosuvastatin on Left Ventricular Remodeling
NCT01223703	PHASE3	COMPLETED	PUFAs and Left Ventricular Function in Heart Failure
NCT01583114	PHASE3	TERMINATED	PREclinical Mutation CARriers From Families With DIlated Cardiomyopathy and ACE Inhibitors
NCT01914081	PHASE3	UNKNOWN	Resveratrol: A Potential Anti- Remodeling Agent in Heart Failure, From Bench to Bedside
NCT02989181	PHASE3	UNKNOWN	Continues Positive Airway Pressure Treatment for Patients With Dilated Cardiomyopathy and Obstructive Sleep Apnea
NCT03439514	PHASE3	TERMINATED	A Study of ARRY-371797 (PF-07265803) in Patients With Symptomatic Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation
NCT05237323	PHASE3	COMPLETED	Micophenolate Mofetil Versus Azathioprine in Myocarditis
NCT05849766	PHASE3	COMPLETED	Effect of Dapagliflozin on Cardiac Structure, Function and Secondary Mitral Regurgitation in Patients with Left Ventricle Dysfunction
NCT06250257	PHASE3	RECRUITING	Bromocriptine in Dilated Cardiomyopathy Among Women of Reproductive Age
NCT06205550	PHASE2	NOT_YET_RECRUITING	N-of-1 in ATS and MEPPC
NCT01648205	PHASE2	COMPLETED	Long-term Efficacy Study of Sodium Channel Blocker in LQT3 Patients
NCT02412709	PHASE2	UNKNOWN	Long QT Syndrome Screening in Newborns
NCT04581408	PHASE2	COMPLETED	Mutation-specific Therapy for the Long QT Syndrome
NCT00629018	PHASE2	COMPLETED	Safety and Efficacy Study of Stem Cell Transplantation to Treat Dilated Cardiomyopathy
NCT00629096	PHASE2	COMPLETED	Intracoronary Infusion of Autologous Bone Marrow Cells for Treatment of Idiopathic Dilated Cardiomyopathy
NCT00765518	PHASE2	COMPLETED	Use of Ixmyelocel-T (Formerly Cardiac Repair Cell [CRC] Treatment) in Patients With Heart Failure Due to Dilated Cardiomyopathy (IMPACT-DCM)
NCT00847964	PHASE2	COMPLETED	Safety and Feasibility of Algisyl-LVR™ as a Method of Left Ventricular Restoration in Patients With DCM Undergoing Open-heart Surgery
NCT01020968	PHASE2	COMPLETED	Use of Ixmyelocel-T (Formerly Catheter-based Cardiac Repair Cell [CRC]) Treatment in Patients With Heart Failure Due to Dilated Cardiomyopathy
NCT01302171	PHASE2	COMPLETED	Bone Marrow Derived Adult Stem Cells for Dilated Cardiomyopathy
NCT01350310	PHASE2	COMPLETED	Safety and Efficacy Study of Intramyocardial Stem Cell Therapy in Patients With Dilated Cardiomyopathy
NCT02133911	PHASE2	COMPLETED	A Pilot Trial of Ranolazine to Treat Patients With Dilated Cardiomyopathy
NCT03071653	PHASE2	SUSPENDED	Left Cardiac Sympathetic Denervation for Cardiomyopathy Feasibility Pilot Study
NCT03572660	PHASE2	ACTIVE_NOT_RECRUITING	Use of Bone Marrow Derived Stem Cell and G-CSF With Circulatory Assistance in the Treatment of DCM