KCNJ3

Summary

KCNJ3 (potassium inwardly rectifying channel subfamily J member 3, HGNC:6264) is a protein-coding gene on chromosome 2q24.1, encoding G protein-activated inward rectifier potassium channel 1 (P48549). Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it.

Potassium channels are present in most mammalian cells, where they participate in a wide range of physiologic responses. The protein encoded by this gene is an integral membrane protein and inward-rectifier type potassium channel. The encoded protein, which has a greater tendency to allow potassium to flow into a cell rather than out of a cell, is controlled by G-proteins and plays an important role in regulating heartbeat. It associates with three other G-protein-activated potassium channels to form a heteromultimeric pore-forming complex that also couples to neurotransmitter receptors in the brain and whereby channel activation can inhibit action potential firing by hyperpolarizing the plasma membrane. These multimeric G-protein-gated inwardly-rectifying potassium (GIRK) channels may play a role in the pathophysiology of epilepsy, addiction, Down’s syndrome, ataxia, and Parkinson’s disease. Alternative splicing results in multiple transcript variants encoding distinct proteins.

Source: NCBI Gene 3760 — RefSeq curated summary.

At a glance

• Gene–disease (curated): epilepsy (Moderate, GenCC)
• GWAS associations: 26
• Clinical variants (ClinVar): 35 total
• Phenotypes (HPO): 11
• Druggable target: yes
• MANE Select transcript: NM_002239

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6264
Approved symbol	KCNJ3
Name	potassium inwardly rectifying channel subfamily J member 3
Location	2q24.1
Locus type	gene with protein product
Status	Approved
Aliases	Kir3.1, GIRK1, KGA
Ensembl gene	ENSG00000162989
Ensembl biotype	protein_coding
OMIM	601534
Entrez	3760

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000295101, ENST00000493505, ENST00000544049, ENST00000651198

RefSeq mRNA: 3 — MANE Select: NM_002239 NM_001260508, NM_001260509, NM_002239

CCDS: CCDS2200, CCDS58733

Canonical transcript exons

ENST00000295101 — 3 exons

Exon	Start	End
ENSE00001070412	154698695	154699477
ENSE00001287690	154854727	154858354
ENSE00003473985	154709603	154709819

Expression profiles

Bgee: expression breadth ubiquitous, 196 present calls, max score 95.05.

FANTOM5 (CAGE): breadth broad, TPM avg 3.5909 / max 522.2506, expressed in 319 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
23126	1.8030	276
23125	0.4253	138
23134	0.3302	87
23130	0.2907	94
23127	0.1794	80
23123	0.1350	66
23131	0.0938	16
23122	0.0806	44
23128	0.0715	33
23133	0.0657	25

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	95.05	gold quality
Brodmann (1909) area 23	UBERON:0013554	94.76	gold quality
middle temporal gyrus	UBERON:0002771	93.47	gold quality
cerebellar cortex	UBERON:0002129	92.57	gold quality
cerebellar hemisphere	UBERON:0002245	92.47	gold quality
cerebellar vermis	UBERON:0004720	92.25	gold quality
cerebellum	UBERON:0002037	92.11	gold quality
postcentral gyrus	UBERON:0002581	91.07	gold quality
right hemisphere of cerebellum	UBERON:0014890	91.01	gold quality
primary visual cortex	UBERON:0002436	90.96	gold quality
superior frontal gyrus	UBERON:0002661	90.80	gold quality
lateral nuclear group of thalamus	UBERON:0002736	90.78	gold quality
parietal lobe	UBERON:0001872	90.76	gold quality
jejunal mucosa	UBERON:0000399	89.63	gold quality
occipital lobe	UBERON:0002021	89.00	gold quality
entorhinal cortex	UBERON:0002728	88.12	gold quality
prefrontal cortex	UBERON:0000451	87.78	gold quality
right atrium auricular region	UBERON:0006631	87.34	gold quality
cardiac atrium	UBERON:0002081	87.13	gold quality
pons	UBERON:0000988	86.84	gold quality
cortical plate	UBERON:0005343	86.05	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	85.84	gold quality
seminal vesicle	UBERON:0000998	85.75	gold quality
frontal cortex	UBERON:0001870	85.40	gold quality
neocortex	UBERON:0001950	84.55	gold quality
renal medulla	UBERON:0000362	84.46	gold quality
cerebral cortex	UBERON:0000956	84.45	gold quality
Brodmann (1909) area 9	UBERON:0013540	84.20	gold quality
right frontal lobe	UBERON:0002810	82.67	gold quality
cardiac muscle of right atrium	UBERON:0003379	82.45	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	79.32
E-GEOD-81608	yes	15.49
E-ENAD-27	yes	7.69
E-ANND-3	yes	4.62
E-MTAB-5061	no	3.51

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

179 targeting KCNJ3, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-1468-3P	99.96	72.74	3797

Literature-anchored findings (GeneRIF, showing 23)

• glutamate residue at the C terminus regulates activity – implications for Andersen Disease (inward rectifier potassium channel 2; IRK2) (PMID:12034888)
• that GIRK channels are important functional effectors of the P2Y(12) receptor in human platelets. (PMID:15142872)
• GIRK1 and GIRK2 channels, but not GIRK3 or GIRK4, may may activate signaling pathways in development of lung cancer (PMID:16109170)
• GIRK1 was overexpressed in breast carcinoma suggesting its involvement in proliferation and oncogenesis and its possible use as a putative pharmaceutical target. (PMID:18498071)
• Sar 1 H79G and Rab 1 S25N mutants efficiently blocked the plasma membrane trafficking of the Kir3.1/Kir3.4 complex however they did not block the Gbeta1gamma2/Kir3.1 interaction. Gbeta1-4 can interact with Kir3.1 in the absence of Kir3.4. (PMID:19135528)
• S385 identified as in vitro phosphorylation site. Mutation of this residue to alanine resulted in reduced sensitivity of Kir3.1* currents to H89 & Forskolin, confirming in vivo role for this novel site of the Kir3.1 channel subunit in regulation by PKA. (PMID:19151997)
• We identified several known single nucleotide polymorphisms in KCNJ3 and KCNJ5, but no mutations in either of the genes. (PMID:20110696)
• The very high abundance of mRNA’s encoding GIRK1 together with the presence of GIRK1 protein suggests a pathophysiological role in breast cancer (PMID:20512921)
• halothane predominantly interferes with Gbetagamma-mediated Kir3 currents, such as those functioning during inhibitory synaptic activity (PMID:21044958)
• Kir3.1 channel is involved in the TLR4-mediated signal at an early event by facilitating the recruitment of TLR4 into lipid raft. (PMID:21420934)
• These data suggest that the KCNJ3 gene is genetically associated with schizophrenia in Asian populations and add further evidence to the “channelopathy theory of psychiatric illnesses”. (PMID:21927946)
• Conformational changes at the Gbetagamma/Kir3 interface were lost when Kir3.1 subunits were replaced. (PMID:23175530)
• In the dorsal horn of the developing rat, K(ir)3.1 and K(ir)3.2 were expressed at mature levels from birth. (PMID:23219908)
• we show that Kir3.1, in the absence of trafficking partner subunits, can exit the endoplasmic reticulum (ER) and reach the Golgi (though not the plasma membrane) (PMID:23368630)
• For KCNJ3 rs7574878, individuals who were heterozygous or homozygous for the rare G allele (TT versus TG+ GG) had a 48% reduction in the odds of reporting preoperative breast pain. (PMID:24392765)
• The findings of this study suggest that variations in KCNJ3 genes are associated with both mild and severe persistent breast pain after breast cancer surgery. (PMID:25599232)
• GIRK1/GIRK4 hetero-tetramers are not activated by Na+, but rather are in a permanent state of high responsiveness to G proteins beta-gamma, suggesting that the GIRK1 subunit functions like a GIRK4 subunit with Na+ permanently bound. (PMID:27074664)
• Results clearly corroborate that overexpression of GIRK1 protein exerts profound effects on wound healing, chemoinvasion and cellular motility in the MCF-7 breast cancer cell line suggesting a role to promote invasion and metastasis. (PMID:27519272)
• these data suggest that patients with estrogen receptor positive breast cancer might be stratified into high risk and low risk groups based on the KCNJ3 levels in the tumor (PMID:27835900)
• Gi/o-coupled muscarinic receptors co-localize with GIRK channel for efficient channel activation (PMID:30240440)
• Mutant KCNJ3 and KCNJ5 Potassium Channels as Novel Molecular Targets in Bradyarrhythmias and Atrial Fibrillation. (PMID:30764634)
• GIRK1 triggers multiple cancer-related pathways in the benign mammary epithelial cell line MCF10A. (PMID:31848385)
• A constricted opening in Kir channels does not impede potassium conduction. (PMID:32541684)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	kcnj3a	ENSDARG00000077165
mus_musculus	Kcnj3	ENSMUSG00000026824
rattus_norvegicus	Kcnj3	ENSRNOG00000005369

Paralogs (15): KCNJ13 (ENSG00000115474), KCNJ5 (ENSG00000120457), KCNJ8 (ENSG00000121361), KCNJ2 (ENSG00000123700), KCNJ1 (ENSG00000151704), KCNJ16 (ENSG00000153822), KCNJ6 (ENSG00000157542), KCNJ15 (ENSG00000157551), KCNJ9 (ENSG00000162728), KCNJ4 (ENSG00000168135), KCNJ10 (ENSG00000177807), KCNJ14 (ENSG00000182324), KCNJ12 (ENSG00000184185), KCNJ11 (ENSG00000187486), KCNJ18 (ENSG00000260458)

Protein

Protein identifiers

G protein-activated inward rectifier potassium channel 1 — P48549 (reviewed: P48549)

Alternative names: Inward rectifier K(+) channel Kir3.1, Potassium channel, inwardly rectifying subfamily J member 3

All UniProt accessions (2): A0A494C0M7, P48549

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. This potassium channel is controlled by G proteins. This receptor plays a crucial role in regulating the heartbeat.

Subunit / interactions. Associates with KCNJ5/GIRK4 or KCNJ6/GIRK2 to form a G-protein activated heteromultimer pore-forming unit. The resulting inward current is much larger. Associates with KCNJ9/GIRK3 to form a G-protein activated heteromultimer pore-forming unit.

Subcellular location. Membrane.

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. KCNJ3 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P48549-1	1	yes
P48549-2	2

RefSeq proteins (3): NP_001247437, NP_001247438, NP_002230* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003274	K_chnl_inward-rec_Kir3.1	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 (22 total): topological domain 4, region of interest 2, modified residue 2, splice variant 2, transmembrane region 2, sequence conflict 2, intramembrane region 2, chain 1, short sequence motif 1, compositionally biased region 1, site 1, glycosylation site 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P48549-F1	72.88	0.49

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): 173 (role in the control of polyamine-mediated channel gating and in the blocking by intracellular magnesium)

Post-translational modifications (2): 385, 424

Glycosylation sites (1): 119

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: 251 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, BENPORATH_ES_WITH_H3K27ME3, GOBP_RESPONSE_TO_ELECTRICAL_STIMULUS, GOBP_CIRCULATORY_SYSTEM_PROCESS, NKX25_02, REACTOME_POTASSIUM_CHANNELS, REACTOME_INWARDLY_RECTIFYING_K_CHANNELS, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GOZGIT_ESR1_TARGETS_DN, GOCC_CELL_SURFACE, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_CELL_CELL_SIGNALING, GOBP_MUSCLE_CONTRACTION, SMID_BREAST_CANCER_LUMINAL_B_UP, GOBP_CELL_COMMUNICATION_INVOLVED_IN_CARDIAC_CONDUCTION

GO Biological Process (13): potassium ion transport (GO:0006813), regulation of monoatomic ion transmembrane transport (GO:0034765), response to electrical stimulus (GO:0051602), 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), regulation of presynaptic membrane potential (GO:0099505)

GO Molecular Function (7): phosphatidylinositol-4,5-bisphosphate binding (GO:0005546), 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 monoatomic ion channel activity involved in regulation of presynaptic membrane potential (GO:0099508), voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization (GO:1902282), inward rectifier potassium channel activity (GO:0005242), protein binding (GO:0005515)

GO Cellular Component (11): plasma membrane (GO:0005886), voltage-gated potassium channel complex (GO:0008076), external side of plasma membrane (GO:0009897), T-tubule (GO:0030315), presynaptic membrane (GO:0042734), parallel fiber to Purkinje cell synapse (GO:0098688), I(KACh) inward rectifier potassium channel complex (GO:1990566), cell surface (GO:0009986), 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
cellular anatomical structure	3
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
response to abiotic stimulus	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
regulation of membrane potential	1
phosphatidylinositol phosphate binding	1
phosphatidylinositol bisphosphate binding	1
inward rectifier potassium channel activity	1
voltage-gated monoatomic ion channel activity	1
presynaptic membrane	1
regulation of presynaptic membrane potential	1
membrane repolarization during ventricular cardiac muscle cell action potential	1
voltage-gated potassium channel activity	1
ligand-gated monoatomic cation channel activity	1
binding	1
membrane	1
cell periphery	1
potassium channel complex	1
plasma membrane protein complex	1
plasma membrane	1
cell surface	1

Protein interactions and networks

STRING

1200 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCNJ3	KCNJ5	P48544	984
KCNJ3	KCNJ9	Q92806	982
KCNJ3	KCNJ6	P48051	978
KCNJ3	SUCLG2	Q96I99	892
KCNJ3	KCND3	Q9UK17	752
KCNJ3	KCNA5	P22460	703
KCNJ3	KCNN2	Q9H2S1	680
KCNJ3	GNG2	P59768	638
KCNJ3	GNB1	P04697	631
KCNJ3	HCN4	Q9Y3Q4	617
KCNJ3	KCNIP2	Q9NS61	613
KCNJ3	ARRB2	P32121	609
KCNJ3	IRX4	P78413	606
KCNJ3	KCNH2	Q12809	604
KCNJ3	KCNQ1	P51787	603

IntAct

5 interactions, top by confidence:

A	B	Type	Score
CRK	KCNJ3	psi-mi:“MI:0407”(direct interaction)	0.440
KCNJ5	ERI3	psi-mi:“MI:0914”(association)	0.350
KCNJ5	KCNJ6	psi-mi:“MI:0914”(association)	0.350

BioGRID (16): KCNJ3 (Affinity Capture-MS), KCNJ3 (Affinity Capture-RNA), GNB1 (Reconstituted Complex), GABBR1 (Affinity Capture-Western), GABBR1 (Affinity Capture-Luminescence), KCNJ3 (Affinity Capture-Western), KCNJ5 (Reconstituted Complex), KCNJ3 (Affinity Capture-Western), KCNJ3 (Affinity Capture-Western), ADRB2 (Affinity Capture-Western), KCNJ3 (Affinity Capture-RNA), KCNJ5 (Phenotypic Enhancement), KCNJ3 (Affinity Capture-MS), KCNJ3 (Protein-peptide), KCNJ3 (Positive Genetic)

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

2 interactions.

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

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	31
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1222 predictions. Top by Δscore:

Variant	Effect	Δscore
2:154699478:G:GG	donor_gain	1.0000
2:154709706:C:G	acceptor_gain	1.0000
2:154709707:A:AG	acceptor_gain	1.0000
2:154854721:TTGTA:T	acceptor_loss	1.0000
2:154854723:GTAG:G	acceptor_loss	1.0000
2:154854725:A:AG	acceptor_gain	1.0000
2:154854725:AG:A	acceptor_gain	1.0000
2:154854726:G:GG	acceptor_gain	1.0000
2:154854726:GG:G	acceptor_gain	1.0000
2:154854726:GGGAT:G	acceptor_gain	1.0000
2:154709601:A:AG	acceptor_gain	0.9900
2:154709602:G:GG	acceptor_gain	0.9900
2:154709602:GTCTC:G	acceptor_gain	0.9900
2:154709705:A:AG	acceptor_gain	0.9900
2:154709707:AATTT:A	acceptor_gain	0.9900
2:154709708:A:G	acceptor_gain	0.9900
2:154709716:C:G	acceptor_gain	0.9900
2:154786152:A:T	donor_gain	0.9900
2:154854725:AGG:A	acceptor_gain	0.9900
2:154854726:GGG:G	acceptor_gain	0.9900
2:154709817:CTGG:C	donor_loss	0.9800
2:154709818:TGG:T	donor_loss	0.9800
2:154709820:G:A	donor_loss	0.9800
2:154709821:T:A	donor_loss	0.9800
2:154709822:GAG:G	donor_loss	0.9800
2:154735857:C:CG	donor_gain	0.9800
2:154735877:G:GG	donor_gain	0.9800
2:154837614:A:AG	acceptor_gain	0.9800
2:154854726:GGGA:G	acceptor_gain	0.9800
2:154699475:AAAG:A	donor_loss	0.9700

AlphaMissense

3314 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:154698926:G:C	G51R	1.000
2:154698926:G:T	G51C	1.000
2:154698927:G:A	G51D	1.000
2:154698927:G:T	G51V	1.000
2:154699013:T:A	W80R	1.000
2:154699013:T:C	W80R	1.000
2:154699015:G:C	W80C	1.000
2:154699015:G:T	W80C	1.000
2:154699058:T:A	W95R	1.000
2:154699058:T:C	W95R	1.000
2:154699079:T:A	W102R	1.000
2:154699079:T:C	W102R	1.000
2:154699142:T:A	C123S	1.000
2:154699142:T:C	C123R	1.000
2:154699143:G:A	C123Y	1.000
2:154699143:G:C	C123S	1.000
2:154699144:C:G	C123W	1.000
2:154699173:C:A	A133D	1.000
2:154699179:T:C	L135P	1.000
2:154699192:G:C	E139D	1.000
2:154699192:G:T	E139D	1.000
2:154699203:C:T	T143I	1.000
2:154699208:G:C	G145R	1.000
2:154699209:G:A	G145D	1.000
2:154699209:G:T	G145V	1.000
2:154699211:T:C	Y146H	1.000
2:154699214:G:T	G147C	1.000
2:154699215:G:A	G147D	1.000
2:154699215:G:T	G147V	1.000
2:154699221:G:C	R149P	1.000

dbSNP variants (sampled 300 via entrez): RS1000016690 (2:154787998 T>C), RS1000032186 (2:154748632 A>G), RS1000041563 (2:154726362 C>A,G,T), RS1000094674 (2:154742763 T>A,G), RS1000100297 (2:154813546 C>T), RS1000112916 (2:154751833 C>T), RS1000127428 (2:154812054 C>T), RS1000158162 (2:154741707 T>TA), RS1000186312 (2:154729176 GTCT>G), RS1000193444 (2:154806935 T>G), RS1000240704 (2:154840704 T>C), RS1000257757 (2:154759760 G>A,C,T), RS1000329556 (2:154788365 T>A), RS1000334290 (2:154844057 T>C), RS1000345286 (2:154760090 A>G)

Disease associations

OMIM: gene MIM:601534 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
epilepsy	Moderate	Autosomal dominant

Mondo (1): epilepsy (MONDO:0005027)

Orphanet (0):

HPO phenotypes

11 total (11 of 11 shown, HPO-id order):

HPO	Term
HP:0001279	Syncope
HP:0001658	Myocardial infarction
HP:0001727	Thromboembolic stroke
HP:0001907	Thromboembolism
HP:0001962	Palpitations
HP:0002094	Dyspnea
HP:0002321	Vertigo
HP:0003546	Exercise intolerance
HP:0005110	Atrial fibrillation
HP:0012378	Fatigue
HP:0100749	Chest pain

GWAS associations

26 associations (top):

Study	Trait	p-value
GCST002463_11	Systemic lupus erythematosus	2.000000e-06
GCST003994_2	Age at voice drop	2.000000e-08
GCST004860_19	Alcoholic chronic pancreatitis	4.000000e-06
GCST005790_86	Rosacea symptom severity	5.000000e-07
GCST005790_87	Rosacea symptom severity	9.000000e-06
GCST006269_1116	General cognitive ability	4.000000e-10
GCST006269_306	General cognitive ability	4.000000e-12
GCST006269_726	General cognitive ability	1.000000e-08
GCST006269_768	General cognitive ability	6.000000e-09
GCST006482_29	Lung function (FEV1/FVC)	3.000000e-08
GCST006482_30	Lung function (FEV1/FVC)	1.000000e-06
GCST006857_2	Leisure-time exercise behaviour	8.000000e-06
GCST006858_2	Leisure-time exercise behaviour (age-stratified)	2.000000e-07
GCST006943_29	Feeling miserable	5.000000e-08
GCST007323_12	Risk-taking tendency (4-domain principal component model)	7.000000e-09
GCST007327_24	Smoking status (ever vs never smokers)	3.000000e-08
GCST007329_12	Automobile speeding propensity	4.000000e-09
GCST007603_31	Smoking initiation	4.000000e-08
GCST008295_4	Number of decayed, missing and filled tooth surfaces or use of dentures	3.000000e-09
GCST008306_26	Dentures	2.000000e-09
GCST008810_80	Smoking initiation (ever regular vs never regular)	2.000000e-08
GCST009144_22	Disease progression in age-related macular degeneration (adjusted for baseline)	9.000000e-06
GCST009391_1005	Metabolite levels	3.000000e-06
GCST009391_1381	Metabolite levels	2.000000e-06
GCST009391_2028	Metabolite levels	7.000000e-06
GCST011703_54	Smoking initiation	4.000000e-10

EFO canonical traits (14, from GWAS)

EFO ID	Trait name
EFO:0007888	age at voice drop
EFO:0009180	rosacea severity measurement
EFO:0004337	intelligence
EFO:0004713	FEV/FVC ratio
EFO:0000483	exercise
EFO:0009598	feeling miserable measurement
EFO:0008579	risk-taking behaviour
EFO:0004318	smoking behavior
EFO:0005670	smoking initiation
EFO:0010078	dentures
EFO:0008336	disease progression measurement
EFO:0010359	lysophosphatidylcholine 18:0 measurement
EFO:0010368	lysophosphatidylethanolamine 18:1 measurement
EFO:0010371	lysophosphatidylethanolamine 22:6 measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D004827	Epilepsy	C10.228.140.490

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL1914277 (SINGLE PROTEIN), CHEMBL3038488 (PROTEIN COMPLEX), CHEMBL3038489 (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 (6 total), top 6:

Ligand	Action	Affinity	Parameter
tertiapin-Q	Antagonist	7.9	pIC50
ML297	Activator	6.7	pEC50
PIP2	Agonist	6.3	pKd
VU0810464	Activation	6.14	pEC50
AZD2927	Channel blocker	5.9	pIC50
Na+	Agonist	1.6	pEC50

Binding affinities (BindingDB)

10 measured of 10 human assays (10 total across all organisms); most potent 10 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
US12084442, Example 18	IC50	30 nM	US-12084442: Naphthyridinone derivatives for the treatment of a disease or disorder
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
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
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

ChEMBL bioactivities

493 potent at pChembl≥5 of 508 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.70	IC50	2	nM	CHEMBL5281961
8.22	IC50	6	nM	CHEMBL5991011
8.10	IC50	8	nM	CHEMBL6049828
8.09	Ki	8.2	nM	CHEMBL4559408
8.05	IC50	9	nM	CHEMBL5287217
8.05	IC50	9	nM	CHEMBL5856252
7.96	IC50	11	nM	CHEMBL5280047
7.96	IC50	11	nM	CHEMBL5933498
7.89	IC50	13	nM	CHEMBL5964704
7.89	IC50	13	nM	CHEMBL5904969
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
7.72	IC50	19	nM	CHEMBL5923594
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	CHEMBL5915351
7.51	IC50	31	nM	CHEMBL5838250
7.50	IC50	32	nM	CHEMBL5931550
7.48	EC50	33	nM	CHEMBL5178783
7.48	IC50	33	nM	CHEMBL5933659
7.47	IC50	34	nM	CHEMBL5833985
7.46	IC50	35	nM	CHEMBL6052790
7.44	IC50	36	nM	CHEMBL5807379
7.43	IC50	37	nM	CHEMBL6061639
7.41	IC50	39	nM	CHEMBL5892629
7.40	IC50	40	nM	CHEMBL5862640
7.39	IC50	41	nM	CHEMBL5769545
7.38	IC50	42	nM	CHEMBL6062266
7.34	IC50	46	nM	CHEMBL5756399
7.33	IC50	47	nM	CHEMBL5958674
7.30	IC50	50	nM	CHEMBL3728819
7.30	IC50	50	nM	CHEMBL5282689
7.28	IC50	52	nM	CHEMBL5784076
7.27	IC50	54	nM	CHEMBL6057807
7.25	IC50	56	nM	CHEMBL5803334
7.23	IC50	59	nM	CHEMBL6036261
7.22	IC50	60	nM	CHEMBL5899305
7.19	EC50	65	nM	CHEMBL4453299
7.19	EC50	64	nM	CHEMBL5192713
7.17	IC50	68	nM	CHEMBL5795552
7.16	EC50	70	nM	CHEMBL2409110

PubChem BioAssay actives

366 with measured affinity, of 997 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
2-(2,4-dichlorophenoxy)-N-[2-(4,4-difluorocyclohexyl)-5-methylpyrazol-3-yl]acetamide	1865719: Activation of GIRK1/2 channel (unknown origin) expressed in HEK293 cells incubated for 6 mins by thallium flux assay	ec50	0.0330	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
2-(2,4-dibromophenoxy)-N-[2-(1,1-dioxothiolan-3-yl)-5-methylpyrazol-3-yl]acetamide	1865719: Activation of GIRK1/2 channel (unknown origin) expressed in HEK293 cells incubated for 6 mins by thallium flux assay	ec50	0.0640	uM
N-(2-cyclohexyl-5-methylpyrazol-3-yl)-2-(4-phenylpyrazol-1-yl)acetamide	1624836: Activation of human GIRK1/2 expressed in HEK293 cells co-expressing rat mGlu8 by thallium flux assay	ec50	0.0650	uM
1-(2-benzyl-5-methylpyrazol-3-yl)-3-(3,4-difluorophenyl)urea	762439: Activation of GIRK1/2 (unknown origin)	ec50	0.0700	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
N-(2-cyclohexyl-5-methylpyrazol-3-yl)-2-[5-(3-fluorophenyl)tetrazol-2-yl]acetamide	1624836: Activation of human GIRK1/2 expressed in HEK293 cells co-expressing rat mGlu8 by thallium flux assay	ec50	0.0810	uM
N-[2-(4,4-difluorocyclohexyl)-5-methylpyrazol-3-yl]-2-(5-phenyltetrazol-2-yl)acetamide	1624836: Activation of human GIRK1/2 expressed in HEK293 cells co-expressing rat mGlu8 by thallium flux assay	ec50	0.0840	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
2-(2,4-dichlorophenoxy)-N-[5-methyl-2-(oxan-4-yl)pyrazol-3-yl]acetamide	1865719: Activation of GIRK1/2 channel (unknown origin) expressed in HEK293 cells incubated for 6 mins by thallium flux assay	ec50	0.0880	uM
N-(2-cyclohexyl-5-methylpyrazol-3-yl)-2-(2,4-dichlorophenoxy)acetamide	1865719: Activation of GIRK1/2 channel (unknown origin) expressed in HEK293 cells incubated for 6 mins by thallium flux assay	ec50	0.0910	uM
N-(2-cyclohexyl-5-methylpyrazol-3-yl)-2-(5-phenyltetrazol-2-yl)acetamide	1624836: Activation of human GIRK1/2 expressed in HEK293 cells co-expressing rat mGlu8 by thallium flux assay	ec50	0.0960	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
N-(2-cyclohexyl-5-methylpyrazol-3-yl)-2-[5-(4-methylphenyl)tetrazol-2-yl]acetamide	1624836: Activation of human GIRK1/2 expressed in HEK293 cells co-expressing rat mGlu8 by thallium flux assay	ec50	0.1110	uM
N-(2-cyclohexyl-5-methylpyrazol-3-yl)-2-(4-phenyltriazol-1-yl)acetamide	1624836: Activation of human GIRK1/2 expressed in HEK293 cells co-expressing rat mGlu8 by thallium flux assay	ec50	0.1160	uM
N-(2-cyclohexyl-5-methylpyrazol-3-yl)-2-[5-(3,4-difluorophenyl)tetrazol-2-yl]acetamide	1624836: Activation of human GIRK1/2 expressed in HEK293 cells co-expressing rat mGlu8 by thallium flux assay	ec50	0.1160	uM
N-(2-cyclohexyl-5-methylpyrazol-3-yl)-2-[5-(3-methoxyphenyl)tetrazol-2-yl]acetamide	1624836: Activation of human GIRK1/2 expressed in HEK293 cells co-expressing rat mGlu8 by thallium flux assay	ec50	0.1170	uM
N-(2-cyclohexyl-5-methylpyrazol-3-yl)-2-[5-(3-methylphenyl)tetrazol-2-yl]acetamide	1624836: Activation of human GIRK1/2 expressed in HEK293 cells co-expressing rat mGlu8 by thallium flux assay	ec50	0.1290	uM
2-(4-bromo-2-chlorophenoxy)-N-[2-(1,1-dioxothiolan-3-yl)-5-methylpyrazol-3-yl]acetamide	1865719: Activation of GIRK1/2 channel (unknown origin) expressed in HEK293 cells incubated for 6 mins by thallium flux assay	ec50	0.1320	uM
2-(2,4-dichlorophenoxy)-N-(5-methyl-2-propan-2-ylpyrazol-3-yl)acetamide	1865719: Activation of GIRK1/2 channel (unknown origin) expressed in HEK293 cells incubated for 6 mins by thallium flux assay	ec50	0.1330	uM
2-(2,4-dichlorophenoxy)-N-[2-(1,1-dioxothiolan-3-yl)-5-methylpyrazol-3-yl]acetamide	1865719: Activation of GIRK1/2 channel (unknown origin) expressed in HEK293 cells incubated for 6 mins by thallium flux assay	ec50	0.1370	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-bis(trifluoromethyl)phenoxy]-N-[2-(1,1-dioxothiolan-3-yl)-5-methylpyrazol-3-yl]acetamide	1865719: Activation of GIRK1/2 channel (unknown origin) expressed in HEK293 cells incubated for 6 mins by thallium flux assay	ec50	0.1460	uM
1-(4-chlorophenyl)-3-[3-(2-methylcyclopropyl)-1-(2,2,2-trifluoroethyl)pyrazol-5-yl]urea	1166626: Activation of GIRK1/2 (unknown origin) by thallium-flux based assay	ec50	0.1500	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
2-(2,5-dichlorophenoxy)-N-[2-(1,1-dioxothiolan-3-yl)-5-methylpyrazol-3-yl]acetamide	1865719: Activation of GIRK1/2 channel (unknown origin) expressed in HEK293 cells incubated for 6 mins by thallium flux assay	ec50	0.1500	uM
1-(3,4-difluorophenyl)-3-(5-methyl-2-phenylpyrazol-3-yl)urea	1166626: Activation of GIRK1/2 (unknown origin) by thallium-flux based assay	ec50	0.1600	uM
N-(2-cyclopentyl-5-methylpyrazol-3-yl)-2-(5-phenyltetrazol-2-yl)acetamide	1624836: Activation of human GIRK1/2 expressed in HEK293 cells co-expressing rat mGlu8 by thallium flux assay	ec50	0.1630	uM
2-(3-chloro-4-fluorophenyl)-N-(2-cyclohexyl-5-methylpyrazol-3-yl)acetamide	1865719: Activation of GIRK1/2 channel (unknown origin) expressed in HEK293 cells incubated for 6 mins by thallium flux assay	ec50	0.1650	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
N-(2-cyclohexyl-5-methylpyrazol-3-yl)-2-[5-(4-methoxyphenyl)tetrazol-2-yl]acetamide	1624836: Activation of human GIRK1/2 expressed in HEK293 cells co-expressing rat mGlu8 by thallium flux assay	ec50	0.1750	uM
N-[2-(cyclohexylmethyl)-5-methylpyrazol-3-yl]-2-(5-phenyltetrazol-2-yl)acetamide	1624836: Activation of human GIRK1/2 expressed in HEK293 cells co-expressing rat mGlu8 by thallium flux assay	ec50	0.1760	uM
N-(2-cyclohexyl-5-methylpyrazol-3-yl)-2-[5-(4-fluorophenyl)tetrazol-2-yl]acetamide	1624836: Activation of human GIRK1/2 expressed in HEK293 cells co-expressing rat mGlu8 by thallium flux assay	ec50	0.1800	uM
1-[3-(cyclopropylmethyl)-1-phenylpyrazol-5-yl]-3-(3-fluorophenyl)urea	762440: Inhibition of GIRK1/4 (unknown origin)	ic50	0.1800	uM
N-(2-cyclohexyl-5-methylpyrazol-3-yl)-2-[5-[3-(trifluoromethyl)phenyl]tetrazol-2-yl]acetamide	1624836: Activation of human GIRK1/2 expressed in HEK293 cells co-expressing rat mGlu8 by thallium flux assay	ec50	0.1830	uM
2-[5-(3-cyanophenyl)tetrazol-2-yl]-N-(2-cyclohexyl-5-methylpyrazol-3-yl)acetamide	1624836: Activation of human GIRK1/2 expressed in HEK293 cells co-expressing rat mGlu8 by thallium flux assay	ec50	0.1830	uM
N-(2-cyclohexyl-5-methylpyrazol-3-yl)-2-[5-(2-fluorophenyl)tetrazol-2-yl]acetamide	1624836: Activation of human GIRK1/2 expressed in HEK293 cells co-expressing rat mGlu8 by thallium flux assay	ec50	0.1870	uM
2-(2,4-dichlorophenoxy)-N-[1-(1,1-dioxothiolan-3-yl)-3-ethylpyrazol-5-yl]acetamide	1865719: Activation of GIRK1/2 channel (unknown origin) expressed in HEK293 cells incubated for 6 mins by thallium flux assay	ec50	0.1870	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-(3,4-difluorophenyl)-3-[2-(4-fluorophenyl)-5-methylpyrazol-3-yl]urea	762439: Activation of GIRK1/2 (unknown origin)	ec50	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-(1-benzyl-3-cyclopropylpyrazol-5-yl)-3-(3-chloro-4-fluorophenyl)urea	762439: Activation of GIRK1/2 (unknown origin)	ec50	0.2100	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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases expression	3
Thallium	increases import, increases transport, affects binding, decreases reaction, increases activity	2
Aflatoxin B1	decreases methylation	2
aristolochic acid I	decreases expression	1
methyleugenol	decreases expression	1
sodium arsenite	affects methylation	1
manganese chloride	increases expression	1
N-acetyl-4-benzoquinoneimine	affects response to substance	1
tertiapin	affects binding, decreases reaction, increases activity, increases import	1
entinostat	affects cotreatment, decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
belinostat	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	decreases expression	1
Panobinostat	affects cotreatment, decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Atropine	affects binding, decreases reaction, increases activity, increases import	1
Cadmium	decreases expression	1
Carbachol	affects binding, decreases reaction, increases activity, increases import	1
Coal	increases abundance, increases expression	1
Copper	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	decreases expression	1
Ethinyl Estradiol	decreases expression	1
Manganese	increases expression	1
Oxygen	increases expression	1
Phenylmercuric Acetate	affects cotreatment, decreases expression	1
Propranolol	increases expression	1

ChEMBL screening assays

53 unique, capped per target: 53 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4392957	Binding	Inhibition of Kir3.1 (unknown origin)	Potassium channel blocking 1,2-bis(aryl)ethane-1,2-diamines active as antiarrhythmic agents. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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
NCT01175954	PHASE4	COMPLETED	Cognitive and Behavioral Effects of Lacosamide
NCT01229735	PHASE4	COMPLETED	Levetiracetam Versus Topiramate as Adjunctive Therapy to Evaluate Efficacy and Safety in Subjects With Refractory Partial Onset Seizures
NCT01244724	PHASE4	TERMINATED	Lexapro for Major Depression in Patients With Epilepsy