KCNN4

Summary

KCNN4 (potassium calcium-activated channel subfamily N member 4, HGNC:6293) is a protein-coding gene on chromosome 19q13.31, encoding Intermediate conductance calcium-activated potassium channel protein 4 (O15554). Intermediate conductance calcium-activated potassium channel that mediates the voltage-independent transmembrane transfer of potassium across the cell membrane through a constitutive interaction with calmodulin which binds the intracellular calcium allowing its opening.

The protein encoded by this gene is part of a potentially heterotetrameric voltage-independent potassium channel that is activated by intracellular calcium. Activation is followed by membrane hyperpolarization, which promotes calcium influx. The encoded protein may be part of the predominant calcium-activated potassium channel in T-lymphocytes. This gene is similar to other KCNN family potassium channel genes, but it differs enough to possibly be considered as part of a new subfamily.

Source: NCBI Gene 3783 — RefSeq curated summary.

At a glance

• Gene–disease (curated): dehydrated hereditary stomatocytosis 2 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 23
• Clinical variants (ClinVar): 186 total — 2 pathogenic, 2 likely-pathogenic
• GTEx eGene: eQTL in 34 tissues, sQTL in 5 (q < 0.05)
• Phenotypes (HPO): 73
• Drug target: yes — 2 curated mechanism-of-action drugs; 2 molecules with ChEMBL bioactivity
• Approved drugs (ChEMBL mechanism of action): 1 — Chlorzoxazone
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.97 (unconstrained)
• MANE Select transcript: NM_002250

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6293
Approved symbol	KCNN4
Name	potassium calcium-activated channel subfamily N member 4
Location	19q13.31
Locus type	gene with protein product
Status	Approved
Aliases	KCa3.1, hSK4, hKCa4, hIKCa1, IK
Ensembl gene	ENSG00000104783
Ensembl biotype	protein_coding
OMIM	602754
Entrez	3783

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 10 protein_coding, 8 nonsense_mediated_decay, 3 retained_intron, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000648319

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 2: 3, TSL 3: 2, TSL 5: 2

ENST00000648319, ENST00000597184, ENST00000598836, ENST00000599107, ENST00000599720, ENST00000600408, ENST00000600909, ENST00000601549, ENST00000648053, ENST00000852944, ENST00000852945, ENST00000852946, ENST00000969511, ENST00000969512, ENST00000969513, ENST00000980013, ENST00001043056, ENST00001043057, ENST00001043058, ENST00001043059, ENST00001043060, ENST00001137154

RefSeq mRNA: 1 — MANE Select: NM_002250 NM_002250

CCDS: CCDS12630

Canonical transcript exons

ENST00000648319 — 9 exons

Exon	Start	End
ENSE00000710931	43772000	43772135
ENSE00000710933	43774192	43774619
ENSE00001355606	43766533	43767089
ENSE00002533195	43776541	43776636
ENSE00003517588	43769442	43769560
ENSE00003560727	43767540	43767707
ENSE00003600564	43769719	43769829
ENSE00003676513	43768963	43769032
ENSE00003838655	43780703	43780973

Expression profiles

Bgee: expression breadth ubiquitous, 200 present calls, max score 94.43.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.3425 / max 340.5101, expressed in 1131 samples.

Highest expression (Bgee): olfactory segment of nasal mucosa, parotid gland, saliva-secreting gland, minor salivary gland, mucosa of transverse colon.

Genetic regulation across tissues (GTEx eQTL / sQTL)

KCNN4 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 34 tissues and its splicing (sQTL) in 5 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 39 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Testis	eqtl	7.4e-68	-0.93	19:43798914:C:G
Whole Blood	eqtl	1.2e-62	+0.48	19:43777746:G:A
Brain Frontal Cortex BA9	eqtl	1.7e-23	-0.72	19:43786083:C:T
Brain Cortex	eqtl	5.6e-22	-0.70	19:43786083:C:T
Esophagus Muscularis	eqtl	4.9e-20	+0.61	19:43852438:G:A
Nerve Tibial	eqtl	2.1e-15	+0.35	19:43779691:G:C
Brain Hypothalamus	eqtl	3.8e-14	-0.57	19:43778566:T:G
Brain Hippocampus	eqtl	1.9e-13	-0.53	19:43787249:T:C
Brain Caudate basal ganglia	eqtl	2.4e-10	-0.32	19:43787249:T:C
Brain Spinal cord cervical c-1	eqtl	3.4e-10	+0.61	19:43779691:G:C
Colon Sigmoid	eqtl	5.3e-10	+0.44	19:43819323:T:C
Brain Nucleus accumbens basal ganglia	eqtl	6.1e-10	+0.40	19:43799275:C:T
Esophagus Gastroesophageal Junction	eqtl	8.1e-10	+0.61	19:43805635:G:A
Brain Putamen basal ganglia	eqtl	5.5e-09	+0.47	19:43786750:G:GT
Adrenal Gland	eqtl	6.4e-09	-0.48	19:43783555:C:T
Brain Substantia nigra	eqtl	1.1e-06	+0.52	19:43777746:G:A
Brain Anterior cingulate cortex BA24	eqtl	1.9e-06	-0.42	19:43789204:T:C
Brain Cerebellar Hemisphere	eqtl	1.2e-05	-0.41	19:43787249:T:C
Brain Cerebellum	eqtl	2.4e-05	-0.41	19:43789204:T:C
Adipose Visceral Omentum	eqtl	2.4e-04	+0.21	19:43780379:C:T

FANTOM5 promoters

4 alternative TSS:

Promoter ID	TPM avg	Samples expressed
181355	8.8171	991
181356	2.1618	662
181357	1.1000	505
181358	0.2636	142

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
olfactory segment of nasal mucosa	UBERON:0005386	94.43	gold quality
parotid gland	UBERON:0001831	94.32	gold quality
saliva-secreting gland	UBERON:0001044	94.17	gold quality
minor salivary gland	UBERON:0001830	93.66	gold quality
mucosa of transverse colon	UBERON:0004991	91.58	gold quality
granulocyte	CL:0000094	90.83	gold quality
skin of leg	UBERON:0001511	90.05	gold quality
trachea	UBERON:0003126	89.89	gold quality
mouth mucosa	UBERON:0003729	89.44	gold quality
skin of abdomen	UBERON:0001416	87.87	gold quality
nasal cavity mucosa	UBERON:0001826	87.85	gold quality
placenta	UBERON:0001987	87.21	gold quality
lymph node	UBERON:0000029	86.56	gold quality
transverse colon	UBERON:0001157	86.45	gold quality
rectum	UBERON:0001052	85.98	gold quality
zone of skin	UBERON:0000014	85.91	gold quality
vermiform appendix	UBERON:0001154	85.82	gold quality
spleen	UBERON:0002106	85.57	gold quality
right uterine tube	UBERON:0001302	84.75	gold quality
tonsil	UBERON:0002372	84.62	gold quality
small intestine Peyer’s patch	UBERON:0003454	84.56	gold quality
monocyte	CL:0000576	84.26	gold quality
prostate gland	UBERON:0002367	84.21	gold quality
leukocyte	CL:0000738	84.17	gold quality
mononuclear cell	CL:0000842	84.07	gold quality
body of stomach	UBERON:0001161	83.95	gold quality
caecum	UBERON:0001153	83.21	gold quality
gall bladder	UBERON:0002110	82.62	gold quality
bone marrow cell	CL:0002092	82.56	gold quality
blood	UBERON:0000178	82.51	gold quality
stomach	UBERON:0000945	81.11	gold quality
colonic epithelium	UBERON:0000397	80.85	gold quality
small intestine	UBERON:0002108	80.59	gold quality
urinary bladder	UBERON:0001255	79.82	gold quality
mucosa of sigmoid colon	UBERON:0004993	79.67	gold quality
colonic mucosa	UBERON:0000317	79.54	gold quality
frontal pole	UBERON:0002795	79.47	gold quality
seminal vesicle	UBERON:0000998	79.41	gold quality
colon	UBERON:0001155	79.29	gold quality
buccal mucosa cell	CL:0002336	79.27	gold quality
bone marrow	UBERON:0002371	79.26	gold quality
endometrium epithelium	UBERON:0004811	79.11	gold quality
large intestine	UBERON:0000059	79.07	gold quality
intestine	UBERON:0000160	78.87	gold quality
paraflocculus	UBERON:0005351	78.85	gold quality
middle frontal gyrus	UBERON:0002702	78.11	gold quality
epithelium of mammary gland	UBERON:0003244	78.00	gold quality
mammary duct	UBERON:0001765	77.68	gold quality
pylorus	UBERON:0001166	76.78	gold quality
right coronary artery	UBERON:0001625	76.36	gold quality
endocervix	UBERON:0000458	76.31	gold quality
fundus of stomach	UBERON:0001160	76.23	gold quality
tendon of biceps brachii	UBERON:0008188	76.18	gold quality
upper lobe of left lung	UBERON:0008952	76.15	gold quality
esophagus mucosa	UBERON:0002469	75.77	gold quality
periodontal ligament	UBERON:0008266	75.57	gold quality
mammary gland	UBERON:0001911	75.46	gold quality
thoracic mammary gland	UBERON:0005200	75.34	gold quality
amniotic fluid	UBERON:0000173	74.72	gold quality
mucosa of stomach	UBERON:0001199	74.68	gold quality
tongue squamous epithelium	UBERON:0006919	74.56	gold quality
sigmoid colon	UBERON:0001159	73.78	gold quality
upper lobe of lung	UBERON:0008948	73.64	gold quality
lower esophagus mucosa	UBERON:0035834	73.55	gold quality
trabecular bone tissue	UBERON:0002483	73.49	gold quality
left coronary artery	UBERON:0001626	73.22	gold quality
nucleus accumbens	UBERON:0001882	73.22	gold quality
left uterine tube	UBERON:0001303	72.94	gold quality
vagina	UBERON:0000996	72.73	gold quality
coronary artery	UBERON:0001621	72.71	gold quality
tibial artery	UBERON:0007610	72.55	gold quality
popliteal artery	UBERON:0002250	72.53	gold quality
muscle layer of sigmoid colon	UBERON:0035805	72.41	gold quality
esophagus	UBERON:0001043	72.30	gold quality
olfactory bulb	UBERON:0002264	72.07	gold quality
type B pancreatic cell	CL:0000169	72.05	gold quality
upper arm skin	UBERON:0004263	72.01	silver quality
superior surface of tongue	UBERON:0007371	71.85	gold quality
aorta	UBERON:0000947	71.01	gold quality
ectocervix	UBERON:0012249	70.99	gold quality
smooth muscle tissue	UBERON:0001135	70.48	gold quality
right lung	UBERON:0002167	70.48	gold quality
ileal mucosa	UBERON:0000331	70.13	silver quality
mucosa of urinary bladder	UBERON:0001259	69.58	silver quality
uterine cervix	UBERON:0000002	69.56	gold quality
subcutaneous adipose tissue	UBERON:0002190	69.55	gold quality
diaphragm	UBERON:0001103	69.42	gold quality
anatomical system	UBERON:0000467	69.32	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	69.23	gold quality
thoracic aorta	UBERON:0001515	69.15	gold quality
ascending aorta	UBERON:0001496	69.06	gold quality
descending thoracic aorta	UBERON:0002345	69.02	gold quality
upper leg skin	UBERON:0004262	68.96	gold quality
multicellular organism	UBERON:0000468	68.92	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	68.92	gold quality
material anatomical entity	UBERON:0000465	68.91	gold quality
duodenum	UBERON:0002114	68.85	gold quality
lower esophagus	UBERON:0013473	68.80	gold quality
lower esophagus muscularis layer	UBERON:0035833	68.78	gold quality
caudate nucleus	UBERON:0001873	68.41	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-10855	yes	987.12
E-MTAB-9841	yes	835.15
E-MTAB-10885	yes	564.93
E-MTAB-6701	yes	119.85
E-ANND-3	yes	10.32

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 70 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Salivary gland	tissue	119.1	not detected
Stomach 1	tissue	31.3	not detected
Bone marrow	tissue	16.3	not detected
Placenta	tissue	12.9	not detected
Prostate	tissue	11.9	not detected
Cervix	tissue	10.5	not detected
Lymph node	tissue	9.7	not detected
Appendix	tissue	9.2	not detected
Colon	tissue	9.1	not detected
Breast	tissue	7.9	not detected
Urinary bladder	tissue	7.7	not detected
Tonsil	tissue	7.1	not detected
Spleen	tissue	6.8	not detected
Seminal vesicle	tissue	6.7	not detected
Vagina	tissue	6.2	not detected
Rectum	tissue	5.4	not detected
Duodenum	tissue	5.3	not detected
Thymus	tissue	4.3
Fallopian tube	tissue	3.3	not detected
Gallbladder	tissue	3.1	not detected
Skin 1	tissue	2.5	not detected
Nucleus accumbens	tissue	2.0
Lung	tissue	2.0	not detected
Small intestine	tissue	1.8	not detected
Choroid plexus	tissue	1.4
Endometrium 1	tissue	1.3	not detected
Epididymis	tissue	1.2	not detected
Adipose tissue	tissue	1.1	not detected
Locus coeruleus	tissue	1.0
Postcentral gyrus	tissue	1.0
Superior colliculi	tissue	0.9
Hippocampus	tissue	0.9	not detected
Olfactory bulb	tissue	0.8
Esophagus	tissue	0.7	not detected
Pituitary gland	tissue	0.6
Testis	tissue	0.6	low
Cerebral cortex	tissue	0.6	not detected
Thalamus	tissue	0.6
Somatosensory cortex	tissue	0.6
Occipital cortex	tissue	0.6
Smooth muscle	tissue	0.5	low
Putamen	tissue	0.5
Skeletal muscle	tissue	0.4	not detected
Midbrain	tissue	0.4
Medulla oblongata	tissue	0.4
Substantia nigra	tissue	0.4
Hippocampal formation	tissue	0.4
Entorhinal cortex	tissue	0.4
Ventral forebrain	tissue	0.4
Temporal cortex	tissue	0.4
Heart muscle	tissue	0.3	not detected
Motor cortex	tissue	0.3
Amygdala	tissue	0.3
Spinal cord	tissue	0.3
Retrosplenial and cingulate cortex	tissue	0.3
Caudate putamen	tissue	0.3
Insular cortex	tissue	0.3
Pons	tissue	0.2
Pancreas	tissue	0.2	not detected
Tongue	tissue	0.2

Brain sub-regions (HPA Brain Atlas): detected in 188; highest nTPM — Blood vessel (5.3), Lateral funiculus (white matter) (3.2), Anterior thalamic nucleus, ventral (2.7), Cervical spinal cord, ventral horn (2.2), Lateral vestibular nucleus (2.0).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): REST

miRNA regulators (miRDB)

Targeting KCNN4 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 44 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-556-3P	99.74	68.75	1203
HSA-MIR-3659	99.70	67.97	694
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-646	99.68	67.84	1645
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-4524A-5P	99.57	71.73	1193
HSA-MIR-4524B-5P	99.57	71.68	1195
HSA-MIR-4325	99.49	72.20	1342
HSA-MIR-133A-3P	99.27	71.53	1270
HSA-MIR-133B	99.27	71.53	1270
HSA-MIR-10399-5P	99.17	69.87	2610
HSA-MIR-6504-3P	99.17	69.31	2891
HSA-MIR-485-5P	99.10	64.78	1889

Functional genomics

gnomAD constraint: pLI 5.88e-08, LOEUF 0.972, missense Z 1.6 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000648319 splits into 3 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
19:43,767,546–43,769,543	129 / 149.4	0.86	no
19:43,769,544–43,774,336	109 / 183.7	0.59	no
19:43,774,337–43,780,861	225 / 240.9	0.93	no

Literature-anchored findings (GeneRIF, showing 40)

• functional role of the intermediate conductance Ca(2+)-activated K(+) channel, hIK1, in HaCaT keratinocytes (PMID:12421833)
• trafficking depends upon a C-terminal leucine zipper (PMID:12493744)
• arachidonic acid (AA) interacts with the pore-lining amino acids, Thr(250) and Val(275) in hIK1, conferring inhibition of hIK1 by AA (PMID:12609997)
• Ca2+-activated Cl- secretion in native human airway epithelia requires activation of Ca2+-dependent basolateral K+ channels (hSK4). (PMID:12612194)
• SK4 is the gene that codes for the Gardos channel in red blood cells. This channel is important pathophysiologically, because it represents the major pathway for cell shrinkage via KCl and water loss that occurs in sickle cell disease. (PMID:12773623)
• K(Ca) channels presenting the pharmacology of SK4 channels are present on both apical and basolateral membranes, but it is the basolateral SK4-like channels that play a major role in calcium-dependent chloride secretion in 16HBE14o- cells. (PMID:14724753)
• the NH(2) terminus of hIK1 contains overlapping leucine zipper and dileucine motifs essential for channel assembly and trafficking to the plasma membrane (PMID:14754884)
• activation of Gardos channel at different oxygen tensions is correlated with changes in passive and active calcium transport and sensitivity to calcium (PMID:15039018)
• stochastic Ca2+ permeabilization rather than Gardos-channel variation is the main determinant selecting which sickle cells dehydrate through Gardos channels in each sickling episode (PMID:15339840)
• We present in this work a structural model of the open IKCa (KCa3.1) channel derived by homology modeling from the MthK channel structure, and used this model to compute the transmembrane potential profile along the channel pore. (PMID:15452196)
• first demonstration that gating of the iKCa1 potassium channel is regulated by beta2-adrenoceptors (PMID:15817638)
• Results describe the subcellular distribution of the canine (cIK1) and the human (hIK1) channel protein in different migrating cells. (PMID:15965951)
• phosphatidylinositol 3-phosphate and these 14 amino acids regulate KCa3.1 channel activity by recruiting an as yet to be defined regulatory subunit that is required for Ca2+ gating of KCa3.1 (PMID:16251351)
• H441 cells express KCNN4 and cellular potassium conductance is important to the control of Na(+) absorption in respiratory epithelium (PMID:16766578)
• KCa3.1 channels are a part of the signaling complex that forms at the IS upon antigen presentation. (PMID:17151145)
• We show that nucleoside diphosphate kinase B (NDPK-B), a mammalian histidine kinase, functions downstream of PI(3)P to activate KCa3.1 by phosphorylating histidine 358 in the carboxyl terminus of KCa3.1. (PMID:17157250)
• Increased activity of IKCa1 channel is necessary for the development of endometrial cancer. (PMID:17310992)
• S6 transmembrane segment of the open KCa3.1 channel contains two functional domains delimited by V282 with MTSEA and MTSET binding leading to a channel inhibition at V275, T278, and V282 and to a steep channel activation at positions A283 and A286 (PMID:17353352)
• KCNN4 activity decines sharply throughout the lifespan of human red blood cells. (PMID:17470662)
• The G(alphas)-coupled adenosine A2A receptor closes KCa3.1, providing a clearly defined mechanism by which adenosine inhibits human lung mast cell migration and degranulation. (PMID:17474152)
• KCa3.1 channels are important in human airway smooth muscle cell proliferation. (PMID:17585114)
• SK4 channels activity, underlying the Ca(2+)-dependent K(+) permeability was in particular increased by IL-13 (PMID:17762175)
• KCNN4 channels, possibly in parallel with volume-sensitive outwardly rectifying Cl channels, effect regulatory volume decrease in lens epithelial cells. (PMID:18184876)
• KCa3.1 and KCa2.3 are translocated out of the endoplasmic reticulum associated with Derlin-1. (PMID:18227067)
• KCa3.1 channels are not immobilized at the front but move in a diffuse way throughout the plasma membrane of migrating cells. (PMID:18287336)
• IK1 channel activity appears to mediate, at least in part, the response of epidermoid cancer cells to cisplatin treatment. (PMID:18367588)
• KCa3.1 channels play a critical role in transcellular chloride secretion and net fluid transport into the kidney cysts of patients with ADPKD by maintaining (PMID:18547995)
• KCa3.1 contributes to atherogenesis in mice and humans (PMID:18688283)
• An NH2-terminal multi-basic RKR motif is required for the ATP-dependent regulation of IK1. (PMID:18690018)
• findings show the G(s)-coupled EP(2) receptor closes K(Ca)3.1 in lung mast cells and attenuates both chemokine- and PGE(2)-dependent lung mast cell migration (PMID:18792407)
• the mammalian protein histidine phosphatase (PHPT-1) directly binds and inhibits KCa3.1 by dephosphorylating histidine 358 on KCa3.1 (PMID:18796614)
• Inhibition of the KCa3.1 channels by AMP-activated protein kinase in human airway epithelial cells. (PMID:19052260)
• overexpression of the IK(Ca1) channel is likely to promote carcinogenesis in human prostate tissue. (PMID:19270724)
• Data show that moderate increases of mitochondrial matrix [Ca(2+)] will cause mtK(Ca)3.1 opening, thus linking inner membrane K(+) permeability and transmembrane potential to Ca(2+) signalling. (PMID:19406468)
• The expression level of K(Ca)3.1 channels was similar in all T cell subsets in multiple sclerosis patients. (PMID:19409928)
• Data show that the class II phosphatidylinositol 3 kinase C2beta (PI3K-C2beta) is activated by the T-cell receptor (TCR) and functions upstream of NDPK-B to activate KCa3.1 channel activity. (PMID:19587117)
• Nitric oxide increases cardiac IK1 by nitrosylation of cysteine 76 of Kir2.1 channels. (PMID:19608980)
• The aim of this study was to investigate the relationship between single-nucleotide polymorphisms (SNPs) in the human KCNN4 gene or haplotypes and the incidence of myocardial infarction or cerebral infarction in Japanese. (PMID:19644414)
• Data demonstrate that bestrophin 1 is localized in the endoplasmic reticulum (ER), where it interacts with the ER-Ca(2+) sensor and can enhance Ca(2+) signaling and activation of Ca(2+)-dependent Cl(-) (TMEM16A) and K(+) (SK4) channels. (PMID:19823864)
• presence of mtKCa3.1 in tumor cell lines using biochemical and electrophysiological approaches (PMID:20036632)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	kcnn4	ENSDARG00000086091
mus_musculus	Kcnn4	ENSMUSG00000054342
rattus_norvegicus	Kcnn4	ENSRNOG00000019440
drosophila_melanogaster	SK	FBGN0029761
caenorhabditis_elegans		WBGENE00007176
caenorhabditis_elegans		WBGENE00008265
caenorhabditis_elegans	kcnl-2	WBGENE00008570
caenorhabditis_elegans		WBGENE00015387

Paralogs (3): KCNN2 (ENSG00000080709), KCNN1 (ENSG00000105642), KCNN3 (ENSG00000143603)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1277957) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 48 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal heart morphology	2
enlarged spleen	2
increased mean corpuscular volume	2
increased spleen weight	2
abnormal systemic arterial blood pressure	1
macrocytosis	1
abnormal rectum morphology	1
abnormal colon morphology	1
abnormal liver morphology	1
small liver	1
abnormal spleen morphology	1
abnormal thymus morphology	1
small thymus	1
enlarged thymus	1
abnormal testis morphology	1
enlarged testis	1
small seminal vesicle	1
abnormal hematopoietic system physiology	1
abnormal digestive system physiology	1
abnormal seminal vesicle morphology	1
abnormal skin morphology	1
abnormal tooth morphology	1
abnormal digit morphology	1
small heart	1
abnormal T cell physiology	1

+23 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Sus scrofa	P58392	97.0%	Diamond
Bos taurus	P58126	93.5%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
LYPD5	protein-coding	284348
ZNF283	protein-coding	284349
SMG9	protein-coding	56006
PLAUR	protein-coding	5329
IRGC	protein-coding	56269
ZNF404	protein-coding	342908
CATED	ncRNA	100505715

Protein

Protein identifiers

Intermediate conductance calcium-activated potassium channel protein 4 — O15554 (reviewed: O15554)

Alternative names: Gardos channel, IKCa1, KCa3.1, Putative Gardos channel, hKCa4

All UniProt accessions (5): O15554, M0QZ70, M0R1J0, M0R2E8, M0R2F1

UniProt curated annotations — full annotation on UniProt →

Function. Intermediate conductance calcium-activated potassium channel that mediates the voltage-independent transmembrane transfer of potassium across the cell membrane through a constitutive interaction with calmodulin which binds the intracellular calcium allowing its opening. The current is characterized by a voltage-independent activation, an intracellular calcium concentration increase-dependent activation and a single-channel conductance of about 25 picosiemens. Also presents an inwardly rectifying current, thus reducing its already small outward conductance of potassium ions, which is particularly the case when the membrane potential displays positive values, above + 20 mV. Controls calcium influx during vascular contractility by being responsible of membrane hyperpolarization induced by vasoactive factors in proliferative vascular smooth muscle cell types. Following calcium influx, the consecutive activation of KCNN4 channel leads to a hyperpolarization of the cell membrane potential and hence an increase of the electrical driving force for further calcium influx promoting sustained calcium entry in response to stimulation with chemotactic peptides. Required for maximal calcium influx and proliferation during the reactivation of naive T-cells. Plays a role in the late stages of EGF-induced macropinocytosis through activation by PI(3)P.

Subunit / interactions. Homodimer. Homotetramer. Heterotetramer of potassium channel proteins. Interacts with MTMR6; this interaction leads to selective dephosphorylation of PI(3)P in a lipid microdomain adjacent to KCNN4, resulting in a decrease of intermediate conductance calcium-activated potassium channel activity. Interacts (via the C-tail domain) with CALM1; the calmodulin binding is constitutive, does not require calcium and mediates calcium-dependent gating and four calmodulin molecules bind to one channel tetramer.

Subcellular location. Cell membrane. Cell projection. Ruffle membrane.

Tissue specificity. Widely expressed in non-excitable tissues.

Post-translational modifications. Phosphorylation at His-358 by NDKB activates the intermediate conductance calcium-activated potassium channel activity, and conversely its dephosphorylation by PHPT1 inhibits this activity.

Disease relevance. Dehydrated hereditary stomatocytosis 2 (DHS2) [MIM:616689] An autosomal dominant hemolytic anemia characterized by primary erythrocyte dehydration. Erythrocytes exhibit decreased total cation and potassium content that are not accompanied by a proportional net gain of sodium and water. Affected individuals typically manifest mild to moderate compensated hemolytic anemia, with an increased erythrocyte mean corpuscular hemoglobin concentration and a decreased osmotic fragility, both of which reflect cellular dehydration. Their red cells exhibit a panel of various shape abnormalities such as elliptocytes, hemighosts, schizocytes, and very rare stomatocytic cells. Complications such as splenomegaly and cholelithiasis, resulting from increased red cell trapping in the spleen and elevated bilirubin levels, respectively, may occur. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. The channel is inhibited by clotrimazole and charybdotoxin but is insensitive to apamin.

Domain organisation. Transmembrane helices S5 and S6 form the ion channel pore, which is surrounded bymembrane embedded helices S1 to S4. The S4-S5 linker, which contains two distinct helices, undergoes conformational changes upon calmodulin binding to open the channel pore.

Induction. Up-regulated by phorbol myristate acetate (PMA) and phytohemagglutinin (PHA) in T-cells.

Similarity. Belongs to the potassium channel KCNN family. KCa3.1/KCNN4 subfamily.

RefSeq proteins (1): NP_002241* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004178	CaM-bd_dom	Domain
IPR013099	K_chnl_dom	Domain
IPR015449	K_chnl_Ca-activ_SK	Family
IPR036122	CaM-bd_dom_sf	Homologous_superfamily

Pfam: PF02888, PF03530, PF07885

Catalyzed reactions (Rhea)

• K(+)(in) = K(+)(out) (RHEA:29463)

UniProt features (36 total): helix 15, transmembrane region 6, turn 4, sequence variant 3, mutagenesis site 2, chain 1, sequence conflict 1, strand 1, intramembrane region 1, region of interest 1, modified residue 1

Structure

Experimental structures (PDB)

17 structures by resolution:

PDB	Title	Method	Resolution (Å)
6D42	Crystal structure of the KCa3.1 C-terminal four-helix bundle (with copper)	X-RAY DIFFRACTION	1.75
9ZRK	Cryo-EM structure of KCa3.1_I/calmodulin channel in complex with SKA111.	ELECTRON MICROSCOPY	2.99
9O48	Cryo-EM structure of the human SK2-4 chimera/calmodulin channel complex in the Ca2+ bound …	ELECTRON MICROSCOPY	3.1
9O5O	Cryo-EM structure of the human SK2-4 chimera/calmodulin channel complex bound to a small …	ELECTRON MICROSCOPY	3.1
9O52	Cryo-EM structure of the human SK2-4 chimera/calmodulin channel complex bound to the bee …	ELECTRON MICROSCOPY	3.18
9O53	Cryo-EM structure of the human SK2-4 chimera/calmodulin channel complex bound to a small …	ELECTRON MICROSCOPY	3.3
9ZRL	Cryo-EM structure of KCa3.1_II/calmodulin channel in complex with SKA111.	ELECTRON MICROSCOPY	3.38
9ZPT	Cryo-EM structure of KCa3.1_II/calmodulin channel in complex with SKA31.	ELECTRON MICROSCOPY	3.39
6CNM	Cryo-EM structure of the human SK4/calmodulin channel complex	ELECTRON MICROSCOPY	3.4
9O51	Cryo-EM structure of the human SK2-4 chimera/calmodulin channel complex in the Ca2+ free …	ELECTRON MICROSCOPY	3.4
9YDZ	Cryo EM structure of KCa3.1_R355K_II/calmodulin channel in complex with rimtuzalcap	ELECTRON MICROSCOPY	3.4
6CNN	Cryo-EM structure of the human SK4/calmodulin channel complex in the Ca2+ bound state I	ELECTRON MICROSCOPY	3.5
9ED1	Cryo-EM structure of the human KCa3.1/calmodulin channel in complex with Ca2+ and …	ELECTRON MICROSCOPY	3.5
9OA8	Cryo-EM structure of KCa3.1/calmodulin channel in complex with NS309	ELECTRON MICROSCOPY	3.59
9ZPO	Cryo-EM structure of KCa3.1_I/calmodulin channel in complex with SKA31.	ELECTRON MICROSCOPY	3.67
6CNO	Cryo-EM structure of the human SK4/calmodulin channel complex in the Ca2+ bound state II	ELECTRON MICROSCOPY	4.7
9Y5Q	Cryo EM structure of KCa3.1_R355K_I/calmodulin channel in complex with rimtuzalcap	ELECTRON MICROSCOPY	4.73

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15554-F1	84.55	0.51

Human Protein Atlas

Protein class: Transporters, Transporter channels and pores, Voltage-gated ion channels, Calcium-Activated Potassium Channels, Predicted membrane proteins, Predicted intracellular proteins, Disease related genes, FDA approved drug targets, Small molecule drugs, Human disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; plasma membrane

Antibody reliability (HPA): IH approved · IF approved

Functional residue map

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

Post-translational modifications (1)

Type	Positions
Phosphohistidine	358

Mutagenesis-validated functional residues (2)

Position	Phenotype
250	loss of sensitivity to triarylmethanes.
275	loss of sensitivity to triarylmethanes.

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 3; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

3 pathways:

ID	Pathway	Evidence
R-HSA-1296052	Ca2+ activated K+ channels	curated
R-HSA-112316	Neuronal System	—
R-HSA-1296071	Potassium Channels	—

MSigDB gene sets: 790 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, GOBP_REGULATION_OF_T_CELL_RECEPTOR_SIGNALING_PATHWAY, GOBP_CHROMOSOME_ORGANIZATION, GOBP_REGULATION_OF_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_DIGESTION, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, GOBP_PINOCYTOSIS, GOBP_PROTEIN_HOMOTETRAMERIZATION, GOBP_REGULATION_OF_NUCLEAR_DIVISION, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, REACTOME_POTASSIUM_CHANNELS, GCM_NPM1, MODULE_64, MORF_UBE2I, GOBP_CELL_CYCLE_PHASE_TRANSITION

GO Biological Process (14): immune system process (GO:0002376), potassium ion transport (GO:0006813), calcium ion transport (GO:0006816), defense response (GO:0006952), stabilization of membrane potential (GO:0030322), macropinocytosis (GO:0044351), positive regulation of T cell receptor signaling pathway (GO:0050862), protein homotetramerization (GO:0051289), potassium ion transmembrane transport (GO:0071805), positive regulation of potassium ion transmembrane transport (GO:1901381), regulation of calcium ion import across plasma membrane (GO:1905664), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220), regulation of transport (GO:0051049)

GO Molecular Function (8): potassium channel activity (GO:0005267), calmodulin binding (GO:0005516), calcium-activated potassium channel activity (GO:0015269), small conductance calcium-activated potassium channel activity (GO:0016286), protein phosphatase binding (GO:0019903), intermediate conductance calcium-activated potassium channel activity (GO:0022894), protein homodimerization activity (GO:0042803), protein binding (GO:0005515)

GO Cellular Component (7): plasma membrane (GO:0005886), voltage-gated potassium channel complex (GO:0008076), vesicle (GO:0031982), ruffle membrane (GO:0032587), neuron projection (GO:0043005), neuronal cell body (GO:0043025), membrane (GO:0016020)

Reactome top-level categories

2 top-level categories:

Category	Pathways
Potassium Channels	1
Neuronal System	1

GO top-level categories

45 GO namespaces:

Category	Terms
metal ion transport	2
transport	2
calcium-activated potassium channel activity	2
biological_process	1
response to stress	1
regulation of membrane potential	1
pinocytosis	1
T cell receptor signaling pathway	1
regulation of T cell receptor signaling pathway	1
positive regulation of antigen receptor-mediated signaling pathway	1
protein homooligomerization	1
protein tetramerization	1
potassium ion transport	1
monoatomic cation transmembrane transport	1
positive regulation of potassium ion transport	1
potassium ion transmembrane transport	1
regulation of potassium ion transmembrane transport	1
positive regulation of cation transmembrane transport	1
regulation of calcium ion import	1
calcium ion import across plasma membrane	1
regulation of calcium ion transmembrane transport	1
monoatomic ion transport	1
transmembrane transport	1
regulation of localization	1
monoatomic cation channel activity	1
potassium ion transmembrane transporter activity	1
protein binding	1
calcium-activated cation channel activity	1
potassium channel activity	1
phosphatase binding	1
identical protein binding	1
protein dimerization activity	1
binding	1
membrane	1
cell periphery	1
potassium channel complex	1
plasma membrane protein complex	1
membrane-bounded organelle	1
ruffle	1
cell projection membrane	1
leading edge membrane	1
plasma membrane bounded cell projection	1
somatodendritic compartment	1
cell body	1
cellular anatomical structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 15 of 29 annotations. The rest are phylogenetic / computational / electronic (IEA).

15 experimentally-supported GO terms:

GO term	NS	Evidence
calcium ion transport	BP	direct assay
macropinocytosis	BP	direct assay
positive regulation of T cell receptor signaling pathway	BP	direct assay
potassium ion transmembrane transport	BP	direct assay
protein homotetramerization	BP	direct assay
regulation of calcium ion import across plasma membrane	BP	direct assay
stabilization of membrane potential	BP	direct assay
plasma membrane	CC	direct assay
ruffle membrane	CC	direct assay
vesicle	CC	direct assay
calcium-activated potassium channel activity	MF	direct assay
calmodulin binding	MF	direct assay
intermediate conductance calcium-activated potassium channel activity	MF	direct assay
protein homodimerization activity	MF	direct assay
protein phosphatase binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 1,220 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCNN4	CSN3	P07498	897
KCNN4	NME2	P22392	877
KCNN4	KCNA3	P22001	851
KCNN4	KCNMA1	Q12791	841
KCNN4	KCNMB4	Q86W47	754
KCNN4	PIEZO1	Q92508	589
KCNN4	TRPV4	Q9HBA0	579
KCNN4	PHPT1	Q9NRX4	573
KCNN4	KCNA2	P16389	570
KCNN4	KCNA1	Q09470	569
KCNN4	CALM1	P02593	567
KCNN4	KCNU1	A8MYU2	565
KCNN4	CALML4	Q96GE6	556
KCNN4	KCNJ2	P48049	551
KCNN4	CALML6	Q8TD86	550

IntAct

Human interaction partners of KCNN4 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

22 partners by confidence:

Partner	Interaction type	MIscore	Records
CFTR	physical association	0.600	5
CALM1	direct interaction	0.590	2
BIK	physical association	0.560	3
CNIH3	physical association	0.560	3
FXYD3	physical association	0.560	3
GPR152	physical association	0.560	3
PMP22	physical association	0.560	3
SLC30A2	physical association	0.560	3
STX1B	physical association	0.560	3
PBXIP1	association	0.530	1
PHPT1	physical association	0.400	2
PRKAG1	physical association	0.370	1
B4GAT1	association	0.350	1
BLOC1S6	association	0.350	1
CASQ2	association	0.350	1
DCAF8L2	association	0.350	1
EIF2B5	association	0.350	1
FEZ1	association	0.350	1
PEX19	association	0.350	1
PGAM2	association	0.350	1
TNNC1	association	0.350	1
TYROBP	association	0.350	1

BioGRID (78 interactions; top human partners by supporting records): CALM1 (Two-hybrid; 3 records), ACKR2 (Affinity Capture-MS), AMHR2 (Affinity Capture-MS), ASPH (Affinity Capture-MS), B4GAT1 (Affinity Capture-MS), BIK (Two-hybrid), BLOC1S6 (Affinity Capture-MS), C3orf52 (Affinity Capture-MS), CACNA1D (FRET), CASQ2 (Affinity Capture-MS), CDH1 (Proximity Label-MS), CNIH3 (Two-hybrid), CREB3 (Affinity Capture-MS), CREB3L3 (Affinity Capture-MS), CXCR4 (Affinity Capture-MS)

SIGNOR signaling

showing 9 of 10 signaling interactions:

A	Effect	B	Mechanism
NME2	up-regulates	KCNN4	phosphorylation
TRAM-34	up-regulates	KCNN4	“chemical activation”
Riluzole	“up-regulates activity”	KCNN4	“chemical activation”
Naphtho[1,2-d]thiazol-2-amine	“up-regulates activity”	KCNN4	“chemical activation”
nitrendipine	“down-regulates activity”	KCNN4	“chemical inhibition”
clotrimazole	“down-regulates activity”	KCNN4	“chemical inhibition”
PRKACA	“down-regulates activity”	KCNN4	phosphorylation
PHPT1	“down-regulates activity”	KCNN4	dephosphorylation
KCNN4	“up-regulates quantity”	calcium(2+)	relocalization

Disease & clinical

Genetic variants

Variant evidence for KCNN4: 186 ClinVar records (4 pathogenic / likely pathogenic); 23 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	2
Uncertain significance	108
Likely benign	33
Benign	24

Top pathogenic / likely-pathogenic (4)

Showing all 4 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
252601	NM_002250.3(KCNN4):c.1055G>A (p.Arg352His)	Pathogenic	criteria provided, multiple submitters, no conflicts	12
978810	NM_002250.3(KCNN4):c.940T>C (p.Ser314Pro)	Pathogenic	criteria provided, single submitter	1
372185	NM_002250.3(KCNN4):c.844G>A (p.Val282Met)	Likely pathogenic	criteria provided, single submitter	2
372186	NM_002250.3(KCNN4):c.845T>A (p.Val282Glu)	Likely pathogenic	criteria provided, single submitter	2

Per-variant reference — Sugi Variant

Explore KCNN4’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 29 predictions of 984):

Position(s)	Effect	Δscore	Sites
19:43767708–43767709	acceptor_loss	1.0000	5
19:43768961–43768962	donor_loss	1.0000	4
19:43769033–43769034	acceptor_loss	1.0000	5
19:43769717–43769718	donor_loss	1.0000	5
19:43771998–43771999	donor_loss	1.0000	5
19:43774636	acceptor_gain	1.0000
19:43767624	donor_gain	0.9900
19:43767708	acceptor_loss	0.9900
19:43767712	acceptor_gain	0.9900
19:43769830	acceptor_gain	0.9900

AlphaMissense

964 missense substitutions predicted likely pathogenic (of 2,732 scored), across 273 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M302	9	0.853	0.983
D255	8	0.974	0.991
F248	8	0.973	0.996
F194	8	0.964	0.996
F301	8	0.942	0.995
F190	8	0.941	0.989
F291	8	0.916	0.987
D370	8	0.890	0.955
M156	8	0.863	0.980
H297	8	0.816	0.974
H118	8	0.806	0.980
W242	7	0.979	0.998
E227	7	0.947	0.987
E111	7	0.922	0.975
C267	7	0.920	0.997
W221	7	0.918	0.995
F351	7	0.916	0.974
E295	7	0.912	0.991
R228	7	0.910	0.978
E45	7	0.902	0.960

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

3 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	unfavorable	1.54e-05
Pancreatic Adenocarcinoma (TCGA)	unfavorable	9.06e-05
Kidney Renal Clear Cell Carcinoma (validation)	unfavorable	0.000144

Disease associations

OMIM: gene MIM:602754 | disease phenotypes: MIM:616689, MIM:194380

GenCC curated gene-disease

3 curated gene-disease records:

Disease	Classification	Inheritance	Records
dehydrated hereditary stomatocytosis 2	Strong	Autosomal dominant	3
dehydrated hereditary stomatocytosis	Supportive	Autosomal dominant
cystic fibrosis	Supportive	Autosomal recessive

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (2 panels, 1 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

2 panels:

Panel	Rating
Rare anaemia	green
Fetal anomalies	amber

Mondo (4): dehydrated hereditary stomatocytosis 2 (MONDO:0014737), dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema (MONDO:0008689), dehydrated hereditary stomatocytosis (MONDO:0017910), cystic fibrosis (MONDO:0009061)

Orphanet (1): Dehydrated hereditary stomatocytosis (Orphanet:3202)

HPO phenotypes

showing 60 of 73 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000246	Sinusitis
HP:0000365	Hearing impairment
HP:0000716	Depression
HP:0000739	Anxiety
HP:0000787	Kidney stone
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0000952	Jaundice
HP:0000969	Edema
HP:0001046	Intermittent jaundice
HP:0001081	Cholelithiasis
HP:0001392	Abnormality of the liver
HP:0001394	Cirrhosis
HP:0001508	Failure to thrive
HP:0001738	Exocrine pancreatic insufficiency
HP:0001744	Splenomegaly
HP:0001878	Hemolytic anemia
HP:0001894	Thrombocytosis
HP:0001900	Increased circulating hemoglobin concentration
HP:0001901	Polycythemia
HP:0001907	Thromboembolism
HP:0001923	Reticulocytosis
HP:0001927	Acanthocytosis
HP:0001930	Nonspherocytic hemolytic anemia
HP:0001972	Macrocytic anemia
HP:0001981	Schistocytosis
HP:0002020	Gastroesophageal reflux
HP:0002024	Malabsorption
HP:0002027	Abdominal pain
HP:0002035	Rectal prolapse
HP:0002099	Asthma
HP:0002105	Hemoptysis
HP:0002107	Pneumothorax
HP:0002110	Bronchiectasis
HP:0002205	Recurrent respiratory infections
HP:0002240	Hepatomegaly
HP:0002570	Steatorrhea
HP:0002724	Recurrent Aspergillus infection
HP:0002726	Recurrent Staphylococcus aureus infection
HP:0002783	Recurrent lower respiratory tract infections
HP:0002842	Recurrent Burkholderia cepacia infection
HP:0002904	Hyperbilirubinemia
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003251	Male infertility
HP:0003265	Neonatal hyperbilirubinemia
HP:0003281	Increased circulating ferritin concentration
HP:0003573	Increased total bilirubin
HP:0003577	Congenital onset
HP:0003593	Infantile onset
HP:0004401	Meconium ileus
HP:0004804	Congenital hemolytic anemia
HP:0004823	Anisopoikilocytosis
HP:0005376	Recurrent Haemophilus influenzae infection
HP:0005502	Increased red cell osmotic fragility
HP:0005518	Increased mean corpuscular volume
HP:0006536	Airway obstruction
HP:0010972	Anemia of inadequate production
HP:0011042	Abnormal circulating potassium concentration
HP:0011463	Childhood onset

GWAS associations

23 associations:

Study	Trait	p-value
GCST90002393_5	Monocyte count	4e-86
GCST90002394_553	Monocyte percentage of white cells	6e-68
GCST90002391_241	Mean corpuscular hemoglobin concentration	6e-43
GCST004609_218	Monocyte percentage of white cells	8e-38
GCST004625_216	Monocyte count	1e-37
GCST004608_214	Granulocyte percentage of myeloid white cells	7e-35
GCST004605_55	Mean corpuscular hemoglobin concentration	1e-27
GCST90002384_59	Hemoglobin	8e-23
GCST90002403_27	Red blood cell count	2e-20
GCST010083_303	Hemoglobin levels	2e-16
GCST90002392_142	Mean corpuscular volume	6e-15
GCST90002407_495	White blood cell count	1e-13
GCST90002401_247	Platelet distribution width	7e-13
GCST90002395_322	Mean platelet volume	3e-12
GCST005992_38	Mean corpuscular hemoglobin concentration	5e-12
GCST90002405_391	Reticulocyte count	8e-11
GCST001937_2	Breast cancer	2e-10
GCST90002383_12	Hematocrit	2e-10
GCST90002399_174	Neutrophil percentage of white cells	2e-10
GCST90002400_360	Plateletcrit	3e-10
GCST004602_151	Mean corpuscular volume	2e-9
GCST004615_108	Hemoglobin concentration	4e-9
GCST006011_59	Mean corpuscular volume	2e-8

EFO canonical traits (from GWAS)

11 canonical traits:

EFO ID	Trait name
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0007997	granulocyte percentage of myeloid white cells
EFO:0007989	monocyte percentage of leukocytes
EFO:0004509	hemoglobin measurement
EFO:0005091	monocyte count
EFO:0004348	hematocrit
EFO:0007990	neutrophil percentage of leukocytes
EFO:0007985	platelet crit
EFO:0007984	platelet component distribution width
EFO:0004305	erythrocyte count
EFO:0007986	reticulocyte count

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
D003550	Cystic Fibrosis	C06.689.202; C08.381.187; C16.320.190; C16.614.213

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4305 (SINGLE PROTEIN), CHEMBL4524132 (PROTEIN FAMILY)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the KCNN4 protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

2 curated-mechanism drugs:

Drug	Modality	Max phase
CHLORZOXAZONE	Small molecule	4
SENICAPOC	Small molecule	3

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 57,011 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

2 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL104	CLOTRIMAZOLE	4	56,839
CHEMBL405821	SENICAPOC	3	172

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

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

Target class: vgic — Calcium- and sodium-activated potassium channels (K_Ca, K_Na)

Most potent curated ligand interactions (20 total), top 20:

Ligand	Action	Affinity	Parameter
maurotoxin	Inhibition	9.0	pIC50
charybdotoxin	Inhibition	8.5	pKd
DHP-103	Channel blocker	8.22	pIC50
NS6180	Inhibition	8.05	pIC50
NS309	Agonist	8.0	pEC50
compound rac-16 [PMID: 15603962]	Inhibition	8.0	pIC50
TRAM-34	Inhibition	8.0	pKd
senicapoc	Inhibition	7.96	pIC50
clotrimazole	Inhibition	7.62	pKd
charybdotoxin-GLU32 analog	Inhibition	7.5	pKd
ASP-0819	Activation	7.03	pEC50
Ca2+	Agonist	7.0	pEC50
SKA-121	Agonist	6.96	pEC50
SKA-111	Agonist	6.95	pEC50
SKA-31	Activator	6.6	pEC50
DC-EBIO	Agonist	6.1	pEC50
nitrendipine	Inhibition	6.1	pKd
riluzole	Activator	5.7	pIC50
EBIO	Agonist	4.5	pEC50
chlorzoxazone	Agonist	4.0	pEC50

Binding affinities (BindingDB)

209 measured of 247 human assays (247 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
methyl N-[1-[4-fluoro-3-(trifluoromethyl)phenyl]cyclopropyl]-N-[[(2R)-1-methylpyrrolidin-2-yl]methyl]carbamate	IC50	8.1 nM	US-20240034717: NOVEL POTASSIUM CHANNEL INHIBITORS
methyl N-(2-amino-2-methylpropyl)-N-[1-[4-fluoro-3-(trifluoromethyl)phenyl]cyclopropyl]carbamate	IC50	8.6 nM	US-20240034717: NOVEL POTASSIUM CHANNEL INHIBITORS
methyl N-[1-[4-fluoro-3-(trifluoromethoxy)phenyl]cyclopropyl]-N-[[(2S)-pyrrolidin-2-yl]methyl]carbamate	IC50	8.7 nM	US-20240034717: NOVEL POTASSIUM CHANNEL INHIBITORS
2-(4-Fluoro-phenyl)-2-(2-fluoro-phenyl)-2-phenyl-acetamide	IC50	9 nM
CHEMBL272039	IC50	10 nM
CHEMBL260736	IC50	13 nM
CHEMBL270704	IC50	14 nM
CHEMBL272040	IC50	14 nM
1-N-(cyclopropylmethyl)-1-N-[1-[4-fluoro-3-(trifluoromethyl)phenyl]cyclopropyl]-2-methylpropane-1,2-diamine	IC50	14 nM	US-20240034717: NOVEL POTASSIUM CHANNEL INHIBITORS
2-[(4S)-4,5,5-tris(2-fluorophenyl)-2-oxo-1,3-oxazolidin-3-yl]acetamide	IC50	15 nM	US-9611232: Oxazolidinone and imidazolidinone compounds
2-[(4S)-4-(2-fluorophenyl)-2-oxo-5,5-diphenyl-1,3-oxazolidin-3-yl]acetamide	IC50	15 nM	US-9611232: Oxazolidinone and imidazolidinone compounds
CHEMBL408700	IC50	15 nM
CHEMBL270071	IC50	15 nM
CHEMBL273092	IC50	15 nM
2-[2-[2-[1-(2-fluorophenyl)tetrazol-5-yl]phenyl]phenoxy]acetonitrile	IC50	16 nM	US-9556132: Tetrazole derivatives and their use as potassium channel modulators
5-[2-[2-(fluoromethyl)phenyl]phenyl]-1-(2-fluorophenyl)tetrazole	IC50	17 nM	US-9556132: Tetrazole derivatives and their use as potassium channel modulators
CHEMBL260953	IC50	17 nM
1-N-cyclobutyl-2-methyl-1-N-[1-[3-(trifluoromethyl)phenyl]cyclopropyl]propane-1,2-diamine	IC50	18 nM	US-20240034717: NOVEL POTASSIUM CHANNEL INHIBITORS
1-((2-chlorophenyl)diphenylmethyl)-1H-pyrazole	IC50	20 nM
CHEMBL406683	IC50	20 nM
2-[(4S)-4-(2-fluorophenyl)-5,5-bis(4-fluorophenyl)-2-oxo-1,3-oxazolidin-3-yl]acetamide	IC50	22 nM	US-9611232: Oxazolidinone and imidazolidinone compounds
1-N-cyclopropyl-2-methyl-1-N-[1-[3-(trifluoromethyl)phenyl]cyclopropyl]propane-1,2-diamine	IC50	24 nM	US-20240034717: NOVEL POTASSIUM CHANNEL INHIBITORS
1-(2-fluorophenyl)-5-[2-[2-(2-methoxyethoxy)phenyl]phenyl]tetrazole	IC50	30 nM	US-9556132: Tetrazole derivatives and their use as potassium channel modulators
CHEMBL261828	IC50	30 nM
CHEMBL261606	IC50	30 nM
CHEMBL270913	IC50	34 nM
5-[2-(2-ethoxyphenyl)phenyl]-1-(2-fluorophenyl)tetrazole	IC50	37 nM	US-9556132: Tetrazole derivatives and their use as potassium channel modulators
4-[[4-fluoro-3-(trifluoromethoxy)phenyl]methyl]-1,1-dioxothieno[3,2-b][1,4]thiazin-3-one	IC50	39 nM	US-9533999: Fused thiazin-3-ones as KCA3.1 inhibitors
CHEMBL3287207	IC50	39 nM
CHEMBL258604	IC50	40 nM
4-[1-[3-(trifluoromethyl)phenyl]ethyl]pyrido[3,2-b][1,4]thiazin-3-one	IC50	41 nM	US-9533999: Fused thiazin-3-ones as KCA3.1 inhibitors
2-[(4S)-4-(2-fluorophenyl)-5,5-bis(3-fluorophenyl)-2-oxo-1,3-oxazolidin-3-yl]acetamide	IC50	42 nM	US-9611232: Oxazolidinone and imidazolidinone compounds
2-[(4S)-4,5,5-tris(4-fluorophenyl)-2-oxo-1,3-oxazolidin-3-yl]acetamide	IC50	45 nM	US-9611232: Oxazolidinone and imidazolidinone compounds
4-[[4-chloro-3-(trifluoromethyl)phenyl]methyl]pyrido[3,2-b][1,4]thiazin-3-one	IC50	46 nM	US-9533999: Fused thiazin-3-ones as KCA3.1 inhibitors
4-[[4-chloro-3-(trifluoromethylsulfonyl)phenyl]methyl]pyrido[3,2-b][1,4]thiazin-3-one	IC50	47 nM	US-9533999: Fused thiazin-3-ones as KCA3.1 inhibitors
ethyl N-(2-amino-2-methylpropyl)-N-[1-[4-fluoro-3-(trifluoromethyl)phenyl]cyclopropyl]carbamate	IC50	47 nM	US-20240034717: NOVEL POTASSIUM CHANNEL INHIBITORS
1-[[4-fluoro-3-(trifluoromethoxy)phenyl]methyl]-4,4-dioxothieno[2,3-b][1,4]thiazin-2-one	IC50	48 nM	US-9533999: Fused thiazin-3-ones as KCA3.1 inhibitors
4-[[4-fluoro-3-(trifluoromethoxy)phenyl]methyl]-1,1-dioxopyrido[3,2-b][1,4]thiazin-3-one	IC50	49 nM	US-9533999: Fused thiazin-3-ones as KCA3.1 inhibitors
4-[[4-chloro-3-(trifluoromethylsulfanyl)phenyl]methyl]pyrido[3,2-b][1,4]thiazin-3-one	IC50	52 nM	US-9533999: Fused thiazin-3-ones as KCA3.1 inhibitors
4-[[3-(trifluoromethoxy)phenyl]methyl]pyrido[3,2-b][1,4]thiazin-3-one	IC50	52 nM	US-9533999: Fused thiazin-3-ones as KCA3.1 inhibitors
ethyl N-[1-[4-fluoro-3-(trifluoromethyl)phenyl]cyclopropyl]-N-[[(2S)-pyrrolidin-2-yl]methyl]carbamate	IC50	52 nM	US-20240034717: NOVEL POTASSIUM CHANNEL INHIBITORS
US9556132, 30	IC50	57 nM	US-9556132: Tetrazole derivatives and their use as potassium channel modulators
1-(2-fluorophenyl)-5-[2-[2-(methoxymethyl)phenyl]phenyl]tetrazole	IC50	58 nM	US-9556132: Tetrazole derivatives and their use as potassium channel modulators
2-[(4S)-5,5-bis(4-fluorophenyl)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]acetamide	IC50	58 nM	US-9611232: Oxazolidinone and imidazolidinone compounds
7-[[4-fluoro-3-(trifluoromethoxy)phenyl]methyl]-[1,3]thiazolo[4,5-b][1,4]thiazin-6-one	IC50	60 nM	US-9533999: Fused thiazin-3-ones as KCA3.1 inhibitors
CHEMBL3287212	IC50	60 nM
ethyl 2-[(4R,5S)-4-(4-fluorophenyl)-2-oxo-5-[3-(trifluoromethyl)phenyl]-1,3-oxazolidin-3-yl]acetate	IC50	62 nM	US-9611232: Oxazolidinone and imidazolidinone compounds
2-[(4S)-4-(2-chlorophenyl)-5,5-bis(4-fluorophenyl)-2-oxo-1,3-oxazolidin-3-yl]acetamide	IC50	63 nM	US-9611232: Oxazolidinone and imidazolidinone compounds
2-[5-[2-(2-methoxyphenyl)phenyl]tetrazol-1-yl]benzonitrile	IC50	64 nM	US-9556132: Tetrazole derivatives and their use as potassium channel modulators
4-[[4-chloro-3-(trifluoromethyl)phenyl]methyl]-6-(hydroxymethyl)pyrido[3,2-b][1,4]thiazin-3-one	IC50	66 nM	US-9533999: Fused thiazin-3-ones as KCA3.1 inhibitors

ChEMBL bioactivities

172 potent at pChembl≥5 of 180 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.22	IC50	6	nM	SENICAPOC
8.09	IC50	8.1	nM	CHEMBL4744833
8.07	IC50	8.6	nM	CHEMBL4749039
8.06	IC50	8.7	nM	CHEMBL4791725
8.05	IC50	9	nM	CHEMBL42205
8.00	IC50	10	nM	CHEMBL272039
7.92	IC50	12	nM	SENICAPOC
7.89	IC50	13	nM	CHEMBL260736
7.85	IC50	14	nM	CHEMBL270704
7.85	IC50	14	nM	CHEMBL272040
7.85	IC50	14	nM	CHEMBL4788143
7.82	IC50	15	nM	CHEMBL408700
7.82	IC50	15	nM	CHEMBL270071
7.82	IC50	15	nM	CHEMBL273092
7.82	IC50	15	nM	CHEMBL5765097
7.82	IC50	15	nM	CHEMBL5981960
7.80	IC50	16	nM	CHEMBL5855158
7.77	IC50	17	nM	CHEMBL260953
7.77	IC50	17	nM	CHEMBL5773163
7.75	IC50	18	nM	CHEMBL4756080
7.70	IC50	20	nM	CHEMBL406683
7.70	IC50	20	nM	CHEMBL498270
7.66	IC50	22	nM	CHEMBL5899835
7.62	IC50	24	nM	CHEMBL4764429
7.52	IC50	30	nM	CHEMBL261828
7.52	IC50	30	nM	CHEMBL261606
7.52	IC50	30	nM	CHEMBL5852642
7.47	IC50	34	nM	CHEMBL270913
7.43	IC50	37	nM	CHEMBL5865173
7.41	IC50	39	nM	CHEMBL3287207
7.41	IC50	39	nM	CHEMBL5783315
7.40	IC50	40	nM	CHEMBL258604
7.39	IC50	41	nM	CHEMBL3287210
7.38	IC50	42	nM	CHEMBL5994146
7.35	IC50	45	nM	CHEMBL6034068
7.34	IC50	46	nM	CHEMBL5775918
7.33	IC50	47	nM	CHEMBL4745327
7.33	IC50	47	nM	CHEMBL5960938
7.32	IC50	48	nM	CHEMBL3287208
7.31	IC50	49	nM	CHEMBL3287205
7.28	IC50	52	nM	CHEMBL3287209
7.28	IC50	52	nM	CHEMBL4743839
7.28	IC50	52	nM	CHEMBL5961215
7.24	IC50	58	nM	CHEMBL5976036
7.24	IC50	57	nM	CHEMBL5876740
7.24	IC50	58	nM	CHEMBL6055879
7.22	IC50	60	nM	CHEMBL3287212
7.22	IC50	60	nM	CHEMBL6058552
7.21	IC50	62	nM	CHEMBL5979285
7.20	IC50	63	nM	CHEMBL5746247

PubChem BioAssay actives

58 with measured affinity, of 110 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
2,2-bis(4-fluorophenyl)-2-phenylacetamide	726263: Inhibition of Kca 3.1 (unknown origin)	ic50	0.0060	uM
methyl N-[1-[4-fluoro-3-(trifluoromethyl)phenyl]cyclopropyl]-N-[[(2R)-1-methylpyrrolidin-2-yl]methyl]carbamate	1678548: Inhibition of Kca3.1 in human erythrocytes	ic50	0.0081	uM
methyl N-(2-amino-2-methylpropyl)-N-[1-[4-fluoro-3-(trifluoromethyl)phenyl]cyclopropyl]carbamate	1678548: Inhibition of Kca3.1 in human erythrocytes	ic50	0.0086	uM
methyl N-[1-[4-fluoro-3-(trifluoromethoxy)phenyl]cyclopropyl]-N-[[(2S)-pyrrolidin-2-yl]methyl]carbamate	1678548: Inhibition of Kca3.1 in human erythrocytes	ic50	0.0087	uM
2-(2-fluorophenyl)-2-(4-fluorophenyl)-2-phenylacetamide	315276: Inhibition of Gardos channel in human RBC assessed as inhibition of ionomycin-stimulated [86Rb] efflux	ic50	0.0090	uM
2-(2-fluorophenyl)-2,2-bis(4-fluorophenyl)acetamide	315276: Inhibition of Gardos channel in human RBC assessed as inhibition of ionomycin-stimulated [86Rb] efflux	ic50	0.0100	uM
2,2,2-tris(3-fluorophenyl)acetamide	315276: Inhibition of Gardos channel in human RBC assessed as inhibition of ionomycin-stimulated [86Rb] efflux	ic50	0.0130	uM
1-N-(cyclopropylmethyl)-1-N-[1-[4-fluoro-3-(trifluoromethyl)phenyl]cyclopropyl]-2-methylpropane-1,2-diamine	1678548: Inhibition of Kca3.1 in human erythrocytes	ic50	0.0140	uM
2-(3,4-difluorophenyl)-2,2-diphenylacetamide	315276: Inhibition of Gardos channel in human RBC assessed as inhibition of ionomycin-stimulated [86Rb] efflux	ic50	0.0140	uM
2,2,2-tris(4-fluorophenyl)acetamide	315276: Inhibition of Gardos channel in human RBC assessed as inhibition of ionomycin-stimulated [86Rb] efflux	ic50	0.0140	uM
2,2-bis(3-fluorophenyl)-2-(4-fluorophenyl)acetamide	315276: Inhibition of Gardos channel in human RBC assessed as inhibition of ionomycin-stimulated [86Rb] efflux	ic50	0.0150	uM
2-(2-fluorophenyl)-2,2-diphenylacetamide	315276: Inhibition of Gardos channel in human RBC assessed as inhibition of ionomycin-stimulated [86Rb] efflux	ic50	0.0150	uM
2,2-bis(2-fluorophenyl)-2-(4-fluorophenyl)acetamide	315276: Inhibition of Gardos channel in human RBC assessed as inhibition of ionomycin-stimulated [86Rb] efflux	ic50	0.0150	uM
2-(3-fluorophenyl)-2,2-bis(4-fluorophenyl)acetamide	315276: Inhibition of Gardos channel in human RBC assessed as inhibition of ionomycin-stimulated [86Rb] efflux	ic50	0.0170	uM
1-N-cyclobutyl-2-methyl-1-N-[1-[3-(trifluoromethyl)phenyl]cyclopropyl]propane-1,2-diamine	1678548: Inhibition of Kca3.1 in human erythrocytes	ic50	0.0180	uM
(2-chlorophenyl)-diphenylmethanamine	315276: Inhibition of Gardos channel in human RBC assessed as inhibition of ionomycin-stimulated [86Rb] efflux	ic50	0.0200	uM
1-[(2-chlorophenyl)-diphenylmethyl]pyrazole	397426: Inhibition of human cloned IK1 expressed in african green monkey COS7 cells by whole cell patch clamp assay	ic50	0.0200	uM
1-N-cyclopropyl-2-methyl-1-N-[1-[3-(trifluoromethyl)phenyl]cyclopropyl]propane-1,2-diamine	1678548: Inhibition of Kca3.1 in human erythrocytes	ic50	0.0240	uM
2,2-bis(3-fluorophenyl)-2-phenylacetamide	315276: Inhibition of Gardos channel in human RBC assessed as inhibition of ionomycin-stimulated [86Rb] efflux	ic50	0.0300	uM
2,2-bis(2-fluorophenyl)-2-phenylacetamide	315276: Inhibition of Gardos channel in human RBC assessed as inhibition of ionomycin-stimulated [86Rb] efflux	ic50	0.0300	uM
2-(2,4-difluorophenyl)-2,2-diphenylacetamide	315276: Inhibition of Gardos channel in human RBC assessed as inhibition of ionomycin-stimulated [86Rb] efflux	ic50	0.0340	uM
4-[1-[4-fluoro-3-(trifluoromethoxy)phenyl]ethyl]-1,1-dioxothieno[3,2-b][1,4]thiazin-3-one	1154717: Inhibition of human KCa3.1 overexpressed in HEK293 cells assessed as thallium influx preincubated for 15 mins followed by thallium/ionomycin addition measured for 50 secs by FLIPR assay	ic50	0.0390	uM
2-(4-fluorophenyl)-2,2-diphenylacetamide	315276: Inhibition of Gardos channel in human RBC assessed as inhibition of ionomycin-stimulated [86Rb] efflux	ic50	0.0400	uM
4-[1-[3-(trifluoromethyl)phenyl]ethyl]pyrido[3,2-b][1,4]thiazin-3-one	1154717: Inhibition of human KCa3.1 overexpressed in HEK293 cells assessed as thallium influx preincubated for 15 mins followed by thallium/ionomycin addition measured for 50 secs by FLIPR assay	ic50	0.0410	uM
ethyl N-(2-amino-2-methylpropyl)-N-[1-[4-fluoro-3-(trifluoromethyl)phenyl]cyclopropyl]carbamate	1678548: Inhibition of Kca3.1 in human erythrocytes	ic50	0.0470	uM
1-[[4-fluoro-3-(trifluoromethoxy)phenyl]methyl]-4,4-dioxothieno[2,3-b][1,4]thiazin-2-one	1154717: Inhibition of human KCa3.1 overexpressed in HEK293 cells assessed as thallium influx preincubated for 15 mins followed by thallium/ionomycin addition measured for 50 secs by FLIPR assay	ic50	0.0480	uM
4-[[4-fluoro-3-(trifluoromethoxy)phenyl]methyl]-1,1-dioxopyrido[3,2-b][1,4]thiazin-3-one	1154717: Inhibition of human KCa3.1 overexpressed in HEK293 cells assessed as thallium influx preincubated for 15 mins followed by thallium/ionomycin addition measured for 50 secs by FLIPR assay	ic50	0.0490	uM
ethyl N-[1-[4-fluoro-3-(trifluoromethyl)phenyl]cyclopropyl]-N-[[(2S)-pyrrolidin-2-yl]methyl]carbamate	1678548: Inhibition of Kca3.1 in human erythrocytes	ic50	0.0520	uM
4-[[3-(trifluoromethoxy)phenyl]methyl]pyrido[3,2-b][1,4]thiazin-3-one	1154717: Inhibition of human KCa3.1 overexpressed in HEK293 cells assessed as thallium influx preincubated for 15 mins followed by thallium/ionomycin addition measured for 50 secs by FLIPR assay	ic50	0.0520	uM
7-[1-[4-fluoro-3-(trifluoromethoxy)phenyl]ethyl]-[1,3]thiazolo[4,5-b][1,4]thiazin-6-one	1154717: Inhibition of human KCa3.1 overexpressed in HEK293 cells assessed as thallium influx preincubated for 15 mins followed by thallium/ionomycin addition measured for 50 secs by FLIPR assay	ic50	0.0600	uM
4-[[4-chloro-3-(trifluoromethyl)phenyl]methyl]-6-(hydroxymethyl)pyrido[3,2-b][1,4]thiazin-3-one	1154717: Inhibition of human KCa3.1 overexpressed in HEK293 cells assessed as thallium influx preincubated for 15 mins followed by thallium/ionomycin addition measured for 50 secs by FLIPR assay	ic50	0.0660	uM
triphenylmethanamine	315276: Inhibition of Gardos channel in human RBC assessed as inhibition of ionomycin-stimulated [86Rb] efflux	ic50	0.0700	uM
Clotrimazole	397426: Inhibition of human cloned IK1 expressed in african green monkey COS7 cells by whole cell patch clamp assay	ic50	0.0700	uM
N-(2-amino-2-methylpropyl)-N-[1-[4-fluoro-3-(trifluoromethyl)phenyl]cyclopropyl]methanesulfonamide	1678548: Inhibition of Kca3.1 in human erythrocytes	ic50	0.0750	uM
methyl N-(2-amino-2-methylpropyl)-N-[1-[4-fluoro-3-(trifluoromethoxy)phenyl]cyclopropyl]carbamate	1678548: Inhibition of Kca3.1 in human erythrocytes	ic50	0.0920	uM
4-[[4-fluoro-3-(trifluoromethoxy)phenyl]methyl]-7,7-dioxo-2-propan-2-yl-[1,3]thiazolo[5,4-b][1,4]thiazin-5-one	1154717: Inhibition of human KCa3.1 overexpressed in HEK293 cells assessed as thallium influx preincubated for 15 mins followed by thallium/ionomycin addition measured for 50 secs by FLIPR assay	ic50	0.0960	uM
methyl 2,2,2-triphenylacetate	315276: Inhibition of Gardos channel in human RBC assessed as inhibition of ionomycin-stimulated [86Rb] efflux	ic50	0.3300	uM
3-[diphenylphosphoryl(phenyl)methyl]pyridine	724065: Inhibition of IK channel (unknown origin)	ic50	0.5000	uM
N-methyl-1,1,1-triphenylmethanamine	315276: Inhibition of Gardos channel in human RBC assessed as inhibition of ionomycin-stimulated [86Rb] efflux	ic50	0.5500	uM
3-[diphenylphosphoryl(pyridin-3-yl)methyl]pyridine	724065: Inhibition of IK channel (unknown origin)	ic50	1.0000	uM
5-(3-chlorobenzoyl)-6H-benzo[d][1]benzazepin-7-one	397426: Inhibition of human cloned IK1 expressed in african green monkey COS7 cells by whole cell patch clamp assay	ic50	1.3000	uM
5-(4-chlorophenyl)sulfonyl-6H-benzo[d][1]benzazepin-7-one	397426: Inhibition of human cloned IK1 expressed in african green monkey COS7 cells by whole cell patch clamp assay	ic50	1.4000	uM
N-tritylethanamine	315276: Inhibition of Gardos channel in human RBC assessed as inhibition of ionomycin-stimulated [86Rb] efflux	ic50	1.7500	uM
3-[diphenylphosphoryl(piperidin-1-yl)methyl]pyridine	724065: Inhibition of IK channel (unknown origin)	ic50	1.8000	uM
5-(4-methylphenyl)sulfonyl-6H-benzo[d][1]benzazepin-7-one	397426: Inhibition of human cloned IK1 expressed in african green monkey COS7 cells by whole cell patch clamp assay	ic50	2.1000	uM
5-thiophen-2-ylsulfonyl-6H-benzo[d][1]benzazepin-7-one	397426: Inhibition of human cloned IK1 expressed in african green monkey COS7 cells by whole cell patch clamp assay	ic50	2.4000	uM
3-[diphenylphosphoryl(propyl)amino]benzonitrile	724065: Inhibition of IK channel (unknown origin)	ic50	2.7000	uM
N,N-dimethyl-1,1,1-triphenylmethanamine	315276: Inhibition of Gardos channel in human RBC assessed as inhibition of ionomycin-stimulated [86Rb] efflux	ic50	3.1500	uM
2-trityl-4,5-dihydro-1,3-oxazole	315276: Inhibition of Gardos channel in human RBC assessed as inhibition of ionomycin-stimulated [86Rb] efflux	ic50	4.3000	uM
1-[2-(3-chlorophenyl)-3-pyridinyl]-N-diphenylphosphorylmethanamine	724065: Inhibition of IK channel (unknown origin)	ic50	4.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	decreases expression	3
Clotrimazole	decreases reaction, increases activity, decreases activity, affects cotreatment	3
Estradiol	decreases expression, affects expression, affects cotreatment	3
7,8-benzoquinoline	increases activity	2
4-chlorobenzo(f)isoquinoline	increases activity	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Benzo(a)pyrene	affects methylation, increases expression	2
Calcium	affects abundance, affects reaction, increases transport	2
Hydrogen Peroxide	increases expression, affects expression	2
Potassium	affects reaction, increases transport, affects transport	2
Tamoxifen	affects expression, affects cotreatment, decreases expression	2
Charybdotoxin	increases activity, decreases activity, decreases reaction	2
Raloxifene Hydrochloride	affects expression, affects cotreatment, decreases expression	2
aristolochic acid I	increases expression	1
TL8-506	affects cotreatment, increases expression	1
propionaldehyde	increases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
beta-lapachone	increases expression	1
arsenite	decreases methylation	1
methylparaben	decreases expression	1
afimoxifene	decreases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	increases expression	1
perfluorooctanoic acid	decreases expression	1
benzo(f)quinoline	increases activity	1
pentanal	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
2-palmitoylglycerol	increases expression	1

ChEMBL screening assays

27 unique, capped per target: 27 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1032478	Binding	Inhibition of human cloned IK1 expressed in african green monkey COS7 cells by whole cell patch clamp assay	Inhibitors of potassium channels KV1.3 and IK-1 as immunosuppressants. — *Bioorg Med Chem Lett*

Cellosaurus cell lines

2 cell lines: 1 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1V2	Abcam HeLa KCNN4 KO	Cancer cell line	Female
CVCL_E9Y2	HEK293-KCNN4-RFP	Transformed cell line	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 303 trials:

NCT	Phase	Status	Title
NCT00157690	Phase 4	COMPLETED	Study of Alendronate to Prevent and Treat Osteoporosis in Cystic Fibrosis Patients
NCT00208078	Phase 4	TERMINATED	Effect of Non-Invasive Ventilation in Cystic Fibrosis Patient With Chronic Respiratory Failure.
NCT00244270	Phase 4	COMPLETED	Cystic Fibrosis and Totally Implantable Vascular Access Devices
NCT00333385	Phase 4	TERMINATED	Continuous Versus Short Infusions of Ceftazidime in Cystic Fibrosis
NCT00411736	Phase 4	COMPLETED	Scandinavian Cystic Fibrosis Azithromycin Study
NCT00418470	Phase 4	TERMINATED	Prolonging the Duration of Peripheral Venous Catheters in Cystic Fibrosis People
NCT00431964	Phase 4	COMPLETED	Effect of Azithromycin on Lung Function in 6-18 Year-olds With Cystic Fibrosis (CF) Not Infected With P. Aeruginosa
NCT00434278	Phase 4	TERMINATED	A Trial of Pulmozyme Withdrawal on Exercise Tolerance in Cystic Fibrosis Subjects With Severe Lung Disease (TOPIC)
NCT00483769	Phase 4	COMPLETED	One Year Glargine Treatment in CFRD Children and Adolescents
NCT00528190	Phase 4	COMPLETED	Treatment of Aspergillus Fumigatus (a Fungal Infection) in Patients With Cystic Fibrosis
NCT00557089	Phase 4	COMPLETED	The Effect of rhDNase on Ventilation Inhomogeneity in Patients With Cystic Fibrosis
NCT00572975	Phase 4	COMPLETED	Malabsorption Blood Test:Toward a Novel Approach to Quantify Steatorrhea
NCT00680316	Phase 4	TERMINATED	A Study of Pulmozyme® (Dornase Alpha) in 3- to 5-Year-Old Patients With Cystic Fibrosis
NCT00685035	Phase 4	COMPLETED	Comparison of Airway Clearance Therapy in Cystic Fibrosis Using the Same VEST Therapy Device But With Different Settings
NCT00744250	Phase 4	TERMINATED	Intraduodenal Aspiration Study to Assess the Bioavailability of Oral Pancrecarb® Compared to Placebo Control
NCT00787917	Phase 4	TERMINATED	An Exploratory Study to Assess Multiple Doses of Omalizumab in Patients With Cystic Fibrosis Complicated by Acute Bronchopulmonary Aspergillosis (ABPA)
NCT00843817	Phase 4	COMPLETED	RhDNase and Biodistribution of PMN Serine Proteases in Cystic Fibrosis Sputum
NCT00890370	Phase 4	COMPLETED	Should Any One Airway Clearance Technique be Recommended for People With Cystic Fibrosis?
NCT00996424	Phase 4	TERMINATED	The Effect of Inhaled N-Acetylcysteine Compared to Normal Saline on Sputum Rheology and Lung Function
NCT01044719	Phase 4	UNKNOWN	Duration of Antibiotics in Infective Exacerbations of Cystic Fibrosis
NCT01100606	Phase 4	COMPLETED	A Study to Evaluate the Mode of Administration and Safety of EUR-1008 (APT-1008) in Infants 1 to 12 Months of Age
NCT01131507	Phase 4	COMPLETED	PR-018: An Open-Label, Safety Extension of Study PR-011
NCT01207245	Phase 4	COMPLETED	Circadian Rhythm In Tobramycin Elimination In Cystic Fibrosis
NCT01323101	Phase 4	COMPLETED	Doxycycline Effects on Inflammation in Cystic Fibrosis
NCT01327703	Phase 4	COMPLETED	Control of Steatorrhea in Participants With Cystic Fibrosis and Exocrine Pancreatic Insufficiency
NCT01377792	Phase 4	COMPLETED	Study of Long-term Treatment With Hypertonic Saline in Patients With Cystic Fibrosis
NCT01400750	Phase 4	COMPLETED	Comparison of 2 Treatment Regimens for Eradication of P Aeruginosa Infection in Children With Cystic Fibrosis
NCT01429259	Phase 4	COMPLETED	Population Pharmacokinetics of Prolonged Infusion Meropenem in Cystic Fibrosis (CF) Children
NCT01608555	Phase 4	COMPLETED	Tobramycin 300 mg Once-a-day (o.d.) Aerosol in Adults With Cystic Fibrosis
NCT01667094	Phase 4	UNKNOWN	A Study Comparing Continuous Infusion Antibiotics to Standard Treatment for Lung Infections in Cystic Fibrosis
NCT01694069	Phase 4	TERMINATED	Continuous Infusion Piperacillin-tazobactam for the Treatment of Cystic Fibrosis
NCT01702415	Phase 4	WITHDRAWN	Zoledronic Acid in Cystic Fibrosis
NCT01712334	Phase 4	COMPLETED	A Study of the Comparable Efficacy and Safety of Pulmozyme (Dornase Alfa) Delivered by the eRapid Nebulizer System in Patients With Cystic Fibrosis
NCT01737983	Phase 4	COMPLETED	Effect of Lactobacillus Reuteri in Cystic Fibrosis
NCT01844778	Phase 4	COMPLETED	Ease of Use and Microbial Contamination of Tobramycin Inhalation Powder (TIP) Versus Nebulised Tobramycin Inhalation Solution (TIS) and Nebulised Colistimethate (COLI)
NCT01880346	Phase 4	COMPLETED	Comparison of Absorption of Vitamin D in Cystic Fibrosis
NCT01882400	Phase 4	COMPLETED	Assessment of Response to Treatment of Osteoporosis With Oral Bisphosphonates in Patients With Muscular Dystrophy
NCT01937325	Phase 4	UNKNOWN	CPET in CF Patients With One G551D Mutation Taking VX770
NCT02015663	Phase 4	TERMINATED	Tobramycin Inhalation Powder (TIP) Administered Once Daily Continuously Versus TIP Administered BID in 28 Day on / 28 Day Off Cycles
NCT02048592	Phase 4	UNKNOWN	Impact of Immunonutrition on the Patients With Cystic Fibrosis
NCT02178540	Phase 4	COMPLETED	Study to Validate the Instructions for Use of TOBI® Podhaler™ in Cystic Fibrosis Patients
NCT02277626	Phase 4	COMPLETED	Electro Flo 5000 and Vest Therapy
NCT02421120	Phase 4	COMPLETED	Population Pharmacokinetics and Safety of Intravenous Ceftolozane/Tazobactam in Adult Cystic Fibrosis Patients
NCT02444234	Phase 4	COMPLETED	Pharmacokinetics of Tedizolid Phosphate in Cystic Fibrosis
NCT02504827	Phase 4	COMPLETED	Steady-state Pharmacokinetics of Ceftazidime/Avibactam in Cystic Fibrosis
NCT02547116	Phase 4	WITHDRAWN	Epidemiology and Treatment of Small-colony Variant Staphylococcus Aureus in Cystic Fibrosis
NCT02677701	Phase 4	COMPLETED	Testing the Effect of Adding Chronic Oral Azithromycin to Inhaled Tobramycin in People With Cystic Fibrosis (CF)
NCT02700282	Phase 4	COMPLETED	Backpack Carrying in Children With Cystic Fibrosis
NCT02823470	Phase 4	TERMINATED	A Pilot Study to Evaluate the Use of Smart Adherence Technology to Measure Lumacaftor/Ivacaftor Adherence in CF Subjects Homozygous for the F508del CFTR Mutation
NCT02823964	Phase 4	COMPLETED	EASY: Extended Access to Sollpura Over Years
NCT02875366	Phase 4	COMPLETED	A Study of the Effects of Lumacaftor/Ivacaftor (LUM/IVA) on Exercise Tolerance in Subjects With Cystic Fibrosis (CF), Homozygous for the F508del-CFTR Mutation
NCT02894684	Phase 4	COMPLETED	Aztreonam for Inhalation Solution (AZLI) for the Treatment of Exacerbations of Cystic Fibrosis
NCT02918409	Phase 4	COMPLETED	IV Colistin for Pulmonary Exacerbations: Improving Safety and Efficacy
NCT03045198	Phase 4	UNKNOWN	Effect of Azithromycin on Fatty Acids in CF
NCT03172793	Phase 4	COMPLETED	Telavancin Pharmacokinetics in Cystic Fibrosis Patients
NCT03256799	Phase 4	COMPLETED	Evaluation of Ivacaftor in Patients Using Ataluren for Nonsense Mutations
NCT03256968	Phase 4	COMPLETED	PTC Study to Evaluate Ataluren in Combination With Ivacaftor
NCT03502070	Phase 4	COMPLETED	Human Factors Study to Validate the User Interface of TOBI Podhaler Using Placebo Capsules
NCT03624101	Phase 4	TERMINATED	Novel Therapeutic Approaches for Treatment of CF Patients With W1282X Premature Termination Codon Mutations
NCT03632525	Phase 4	COMPLETED	Intravenous Iron in Adults With Cystic Fibrosis

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for KCNN4 across ~30M SureChEMBL compounds — explore on Sugi Predict.