KCNMB3

Summary

KCNMB3 (potassium calcium-activated channel subfamily M regulatory beta subunit 3, HGNC:6287) is a protein-coding gene on chromosome 3q26.32, encoding Calcium-activated potassium channel subunit beta-3 (Q9NPA1). Regulatory subunit of the calcium activated potassium KCNMA1 (maxiK) channel.

MaxiK channels are large conductance, voltage and calcium-sensitive potassium channels which are fundamental to the control of smooth muscle tone and neuronal excitability. MaxiK channels can be formed by 2 subunits: the pore-forming alpha subunit and the modulatory beta subunit. The protein encoded by this gene is an auxiliary beta subunit which may partially inactivate or slightly decrease the activation time of MaxiK alpha subunit currents. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 22.

Source: NCBI Gene 27094 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 50 total
• MANE Select transcript: NM_171830

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6287
Approved symbol	KCNMB3
Name	potassium calcium-activated channel subfamily M regulatory beta subunit 3
Location	3q26.32
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000171121
Ensembl biotype	protein_coding
OMIM	605222
Entrez	27094

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 nonsense_mediated_decay

ENST00000314235, ENST00000349697, ENST00000392685, ENST00000392686, ENST00000485523, ENST00000486944, ENST00000497599

RefSeq mRNA: 5 — MANE Select: NM_171830 NM_001163677, NM_014407, NM_171828, NM_171829, NM_171830

CCDS: CCDS3225, CCDS3226, CCDS43172, CCDS43173, CCDS54683

Canonical transcript exons

ENST00000392685 — 3 exons

Exon	Start	End
ENSE00001128503	179244495	179244693
ENSE00001512758	179250743	179251114
ENSE00001947263	179242771	179243284

Expression profiles

Bgee: expression breadth ubiquitous, 135 present calls, max score 80.10.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3633 / max 100.4753, expressed in 138 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
39909	0.5039	157
39910	0.3633	138
45717	0.0055	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primary visual cortex	UBERON:0002436	80.10	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.97	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	75.90	gold quality
body of pancreas	UBERON:0001150	75.86	gold quality
spleen	UBERON:0002106	75.40	gold quality
placenta	UBERON:0001987	74.49	gold quality
quadriceps femoris	UBERON:0001377	73.49	gold quality
sural nerve	UBERON:0015488	72.81	gold quality
apex of heart	UBERON:0002098	72.78	gold quality
metanephros cortex	UBERON:0010533	72.54	gold quality
cortex of kidney	UBERON:0001225	72.52	gold quality
subcutaneous adipose tissue	UBERON:0002190	72.37	gold quality
right lobe of liver	UBERON:0001114	72.25	gold quality
pancreas	UBERON:0001264	72.20	gold quality
adipose tissue	UBERON:0001013	71.73	gold quality
ventricular zone	UBERON:0003053	71.68	gold quality
thymus	UBERON:0002370	71.53	silver quality
lower esophagus muscularis layer	UBERON:0035833	71.34	gold quality
lower esophagus	UBERON:0013473	71.32	gold quality
muscle layer of sigmoid colon	UBERON:0035805	71.30	gold quality
thoracic mammary gland	UBERON:0005200	71.22	gold quality
cerebellar vermis	UBERON:0004720	71.20	gold quality
descending thoracic aorta	UBERON:0002345	71.19	gold quality
omental fat pad	UBERON:0010414	71.16	gold quality
body of stomach	UBERON:0001161	71.13	gold quality
ascending aorta	UBERON:0001496	70.58	gold quality
right adrenal gland cortex	UBERON:0035827	70.57	gold quality
thoracic aorta	UBERON:0001515	70.55	gold quality
left coronary artery	UBERON:0001626	70.50	gold quality
bone marrow cell	CL:0002092	70.49	silver quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-MTAB-6386	no	238.45
E-ANND-3	no	2.06

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

12 targeting KCNMB3, 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-580-3P	99.67	69.23	1841
HSA-MIR-3136-3P	99.57	66.59	781
HSA-MIR-7155-3P	99.57	66.48	794
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-451B	99.55	68.28	1380
HSA-MIR-217-5P	99.49	69.93	1419
HSA-MIR-6807-3P	99.15	69.23	1275
HSA-MIR-384	98.71	67.34	1229
HSA-MIR-10226	98.25	66.50	811
HSA-MIR-34C-3P	98.11	65.60	858
HSA-MIR-514A-3P	96.43	67.77	1048
HSA-MIR-514B-3P	96.43	67.77	1048

Literature-anchored findings (GeneRIF, showing 5)

• The frequency of the delA750 mutation was significantly increased in idiopathic generalized epilepsy (7.9%) compared to that in the controls (5.5%; P = 0.016, one-sided; OR = 1.52; 95%-CI: 1.05-2.21). (PMID:16958040)
• The KCNMB3 isoforms beta3a-d may have unique functions in primates. (PMID:18591419)
• Report beta subunit (KNMB1-4)-specific modulations of BK channel function by a Slo1 mutation associated with epilepsy and dyskinesia. (PMID:19204046)
• Single-nucleotide polymorphism in KCNMB3 gene is associated with Insulin Resistance. (PMID:23826284)
• The results from the present study suggested that BK channels modulated the activation state of spinal microglia, and that KCNMB3 is a potential therapeutic target for neuropathic pain. (PMID:31364720)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	kcnmb3	ENSDARG00000063129
mus_musculus	Kcnmb3	ENSMUSG00000091091
rattus_norvegicus	Kcnmb3	ENSRNOG00000027836

Paralogs (3): KCNMB4 (ENSG00000135643), KCNMB1 (ENSG00000145936), KCNMB2 (ENSG00000197584)

Protein

Protein identifiers

Calcium-activated potassium channel subunit beta-3 — Q9NPA1 (reviewed: Q9NPA1)

Alternative names: BK channel subunit beta-3, Calcium-activated potassium channel, subfamily M subunit beta-3, Charybdotoxin receptor subunit beta-3, K(VCA)beta-3, Maxi K channel subunit beta-3, Slo-beta-3

All UniProt accessions (2): A0A087WV41, Q9NPA1

UniProt curated annotations — full annotation on UniProt →

Function. Regulatory subunit of the calcium activated potassium KCNMA1 (maxiK) channel. Modulates the calcium sensitivity and gating kinetics of KCNMA1, thereby contributing to KCNMA1 channel diversity. Alters the functional properties of the current expressed by the KCNMA1 channel. Isoform 2, isoform 3 and isoform 4 partially inactivate the current of KCNBMA. Isoform 4 induces a fast and incomplete inactivation of KCNMA1 channel that is detectable only at large depolarizations. In contrast, isoform 1 does not induce detectable inactivation of KCNMA1. Two or more subunits of KCNMB3 are required to block the KCNMA1 tetramer.

Subunit / interactions. Interacts with KCNMA1 tetramer. There are probably 4 molecules of KCMNB3 per KCNMA1 tetramer.

Subcellular location. Membrane.

Tissue specificity. Isoform 1, isoform 3 and isoform 4 are widely expressed. Isoform 2 is expressed placenta, pancreas, kidney and heart. Isoform 1 and isoform 3 are highly expressed in pancreas and testis.

Post-translational modifications. N-glycosylated. The extracellular domain contains disulfide bond essential for the gating mechanism.

Domain organisation. Isoform 4 cytoplasmic N-terminal domain participates in the partial inactivation of KCNMA1, possibly by binding to a receptor site. The extracellular domain forms gates to block ion permeation, providing a mechanism by which current can be rapidly diminished upon cellular repolarization.

Similarity. Belongs to the KCNMB (TC 8.A.14.1) family. KCNMB3 subfamily.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9NPA1-1	1, 3d	yes
Q9NPA1-2	2, 3a
Q9NPA1-3	3, 3c
Q9NPA1-4	4, 3b
Q9NPA1-5	5

RefSeq proteins (5): NP_001157149, NP_055222, NP_741979, NP_741980, NP_741981* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003930	K_chnl_Ca-activ_BK_bsu	Family

Pfam: PF03185

UniProt features (19 total): splice variant 6, sequence variant 5, topological domain 3, transmembrane region 2, chain 1, sequence conflict 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NPA1-F1	71.99	0.07

Functional residue map

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

Glycosylation sites (1): 131

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-1296052	Ca2+ activated K+ channels
R-HSA-418457	cGMP effects
R-HSA-109582	Hemostasis
R-HSA-112316	Neuronal System
R-HSA-1296071	Potassium Channels
R-HSA-392154	Nitric oxide stimulates guanylate cyclase
R-HSA-418346	Platelet homeostasis

MSigDB gene sets: 212 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, GOBP_CIRCULATORY_SYSTEM_PROCESS, REACTOME_POTASSIUM_CHANNELS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, TGACCTY_ERR1_Q2, chr3q26, CAGCTG_AP4_Q5, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_RESPONSE_TO_METAL_ION, GOBP_REGULATION_OF_ANATOMICAL_STRUCTURE_SIZE, ATF1_Q6, BRN2_01, GOBP_REGULATION_OF_SYSTEM_PROCESS, GOBP_REGULATION_OF_VASOCONSTRICTION

GO Biological Process (7): action potential (GO:0001508), detection of calcium ion (GO:0005513), potassium ion transport (GO:0006813), neuronal action potential (GO:0019228), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220), potassium ion transmembrane transport (GO:0071805)

GO Molecular Function (2): calcium-activated potassium channel activity (GO:0015269), potassium channel regulator activity (GO:0015459)

GO Cellular Component (3): plasma membrane (GO:0005886), voltage-gated potassium channel complex (GO:0008076), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Potassium Channels	1
Nitric oxide stimulates guanylate cyclase	1
Neuronal System	1
Platelet homeostasis	1
Hemostasis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
potassium channel activity	2
regulation of membrane potential	1
detection of chemical stimulus	1
response to calcium ion	1
metal ion transport	1
action potential	1
transmission of nerve impulse	1
transport	1
monoatomic ion transport	1
transmembrane transport	1
potassium ion transport	1
monoatomic cation transmembrane transport	1
calcium-activated cation channel activity	1
ion channel regulator activity	1
membrane	1
cell periphery	1
potassium channel complex	1
plasma membrane protein complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

320 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCNMB3	KCNMA1	Q12791	955
KCNMB3	CLCN2	P51788	795
KCNMB3	BHLHE23	Q8NDY6	570
KCNMB3	LRRC26	Q2I0M4	506
KCNMB3	LRRC38	Q5VT99	505
KCNMB3	LRRC52	Q8N7C0	479
KCNMB3	LRRC55	Q6ZSA7	475
KCNMB3	SPINK14	Q6IE38	464
KCNMB3	KCNN1	Q92952	404
KCNMB3	CTIF	O43310	382
KCNMB3	KCNN4	O15554	373
KCNMB3	CSN3	P07498	357
KCNMB3	A0A0B4J1T7	A0A0B4J1T7	337
KCNMB3	KCNN3	Q9UGI6	326
KCNMB3	KCNN2	Q9H2S1	314

IntAct

2 interactions, top by confidence:

A	B	Type	Score
KCNMB3	UPK3BL1	psi-mi:“MI:0914”(association)	0.350

BioGRID (53): ATP11C (Affinity Capture-MS), XYLT2 (Affinity Capture-MS), ATP2A3 (Affinity Capture-MS), ZMPSTE24 (Affinity Capture-MS), ATP13A2 (Affinity Capture-MS), BTN2A2 (Affinity Capture-MS), SMPD2 (Affinity Capture-MS), PDZD8 (Affinity Capture-MS), NCAPG (Affinity Capture-MS), LCLAT1 (Affinity Capture-MS), POMGNT1 (Affinity Capture-MS), PDE3B (Affinity Capture-MS), SLC12A4 (Affinity Capture-MS), CTDNEP1 (Affinity Capture-MS), ANO6 (Affinity Capture-MS)

ESM2 similar proteins: A1L272, A2RV80, A4IF30, A6QL92, A6QPI1, O02777, O80605, P17200, P20272, P21554, P47746, P51810, P56971, P70259, Q1LZI2, Q2V4F9, Q3TDN0, Q3UGM2, Q4R794, Q5F383, Q5FVJ3, Q5IS73, Q5R4D7, Q5R6J3, Q5RD30, Q66H88, Q6P0E8, Q6P499, Q6R5J2, Q71SP5, Q8BGN5, Q8BZK4, Q8CBH5, Q8IY50, Q8NA31, Q8NBV4, Q8R314, Q8RWF4, Q8WV83, Q91WB2

Diamond homologs: A7VL23, O46372, P97678, Q16558, Q28067, Q28266, Q811Q0, Q86W47, Q8CAE3, Q98855, Q9CZM9, Q9ESK8, Q9JIN6, Q9NPA1, Q9Y691

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	27
Likely benign	2
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

506 predictions. Top by Δscore:

Variant	Effect	Δscore
3:179244697:CAATT:C	acceptor_gain	1.0000
3:179244701:T:C	acceptor_gain	1.0000
3:179244701:T:TC	acceptor_gain	1.0000
3:179244692:TG:T	acceptor_gain	0.9900
3:179244694:C:CC	acceptor_gain	0.9900
3:179244698:A:T	acceptor_gain	0.9900
3:179244699:A:AC	acceptor_gain	0.9900
3:179244700:T:C	acceptor_gain	0.9900
3:179244700:T:TC	acceptor_gain	0.9900
3:179250737:TCTTA:T	donor_loss	0.9900
3:179250738:CTTA:C	donor_loss	0.9900
3:179250739:TTACC:T	donor_loss	0.9900
3:179250740:TACC:T	donor_loss	0.9900
3:179250741:A:AG	donor_loss	0.9900
3:179243285:C:CC	acceptor_gain	0.9800
3:179244691:ATG:A	acceptor_gain	0.9800
3:179244699:A:C	acceptor_gain	0.9800
3:179250083:CTAT:C	donor_gain	0.9800
3:179250084:TATT:T	donor_gain	0.9800
3:179250086:T:C	donor_gain	0.9800
3:179243293:A:C	acceptor_gain	0.9700
3:179244693:GC:G	acceptor_loss	0.9700
3:179245445:T:TG	acceptor_gain	0.9700
3:179250089:A:AC	donor_gain	0.9700
3:179250090:C:CC	donor_gain	0.9700
3:179243283:CA:C	acceptor_gain	0.9600
3:179244689:GAATG:G	acceptor_gain	0.9600
3:179251391:TTCAC:T	donor_loss	0.9600
3:179251392:TCA:T	donor_loss	0.9600
3:179251393:CA:C	donor_loss	0.9600

AlphaMissense

1827 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:179243186:A:C	F186L	0.946
3:179243186:A:T	F186L	0.946
3:179243188:A:G	F186L	0.946
3:179243279:A:C	F155L	0.938
3:179243279:A:T	F155L	0.938
3:179243281:A:G	F155L	0.938
3:179243213:G:C	F177L	0.937
3:179243213:G:T	F177L	0.937
3:179243215:A:G	F177L	0.937
3:179243098:A:G	W216R	0.931
3:179243098:A:T	W216R	0.931
3:179243073:C:T	G224D	0.905
3:179243177:G:C	F189L	0.905
3:179243177:G:T	F189L	0.905
3:179243179:A:G	F189L	0.905
3:179243284:A:G	C154R	0.903
3:179250804:C:G	G67R	0.900
3:179243283:C:G	C154S	0.898
3:179243284:A:T	C154S	0.898
3:179243210:G:C	F178L	0.885
3:179243210:G:T	F178L	0.885
3:179243212:A:G	F178L	0.885
3:179243074:C:G	G224R	0.881
3:179243187:A:C	F186C	0.880
3:179250818:C:T	G62E	0.880
3:179243180:G:C	C188W	0.879
3:179243061:A:T	V228D	0.875
3:179243076:C:T	G223D	0.875
3:179250819:C:G	G62R	0.873
3:179250819:C:T	G62R	0.873

dbSNP variants (sampled 300 via entrez): RS1000222061 (3:179245522 G>C,T), RS1000319092 (3:179264739 G>A), RS1000350331 (3:179264501 C>T), RS1000429535 (3:179256645 A>G), RS1000589543 (3:179250611 T>C), RS1000638077 (3:179264702 C>T), RS1000684225 (3:179250790 T>C), RS1000794199 (3:179241938 C>T), RS1001351396 (3:179263267 A>C,G), RS1001424379 (3:179263882 T>G), RS1001516290 (3:179242735 A>G,T), RS1001583085 (3:179249082 G>A,C), RS1001614198 (3:179248796 T>G), RS1001770558 (3:179264228 A>G), RS1001837581 (3:179255057 C>T)

Disease associations

OMIM: gene MIM:605222 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs7625907	KCNMB2		0.00	0
rs7624046	KCNMB2		0.00	0
rs9839376	KCNMB2		0.00	0

CTD chemical–gene interactions

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, affects cotreatment, decreases methylation	2
trichostatin A	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Arsenic	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Cadmium	increases abundance, increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	increases abundance, increases expression	1

Clinical trials (associated diseases)

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