KCNMB2

Summary

KCNMB2 (potassium calcium-activated channel subfamily M regulatory beta subunit 2, HGNC:6286) is a protein-coding gene on chromosome 3q26.32, encoding Calcium-activated potassium channel subunit beta-2 (Q9Y691). 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 decreases the activation time of MaxiK alpha subunit currents. Alternative splicing results in multiple transcript variants of this gene. Additional variants are discussed in the literature, but their full length nature has not been described.

Source: NCBI Gene 10242 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 34 total
• MANE Select transcript: NM_181361

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6286
Approved symbol	KCNMB2
Name	potassium calcium-activated channel subfamily M regulatory beta subunit 2
Location	3q26.32
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000197584
Ensembl biotype	protein_coding
OMIM	605214
Entrez	10242

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 7 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000358316, ENST00000420517, ENST00000422927, ENST00000432997, ENST00000436247, ENST00000437510, ENST00000452583, ENST00000455865, ENST00000470361, ENST00000894538

RefSeq mRNA: 3 — MANE Select: NM_181361 NM_001278911, NM_005832, NM_181361

CCDS: CCDS3223

Canonical transcript exons

ENST00000452583 — 5 exons

Exon	Start	End
ENSE00001329034	178828178	178828373
ENSE00001735875	178842653	178844429
ENSE00003539820	178807343	178807465
ENSE00003638432	178825588	178825758
ENSE00003846378	178536436	178536711

Expression profiles

Bgee: expression breadth ubiquitous, 156 present calls, max score 91.46.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4479 / max 177.1125, expressed in 76 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
39909	0.5039	157
39911	0.3647	33
39910	0.3633	138
39908	0.0803	40
39914	0.0029	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	91.46	gold quality
right uterine tube	UBERON:0001302	86.53	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.54	silver quality
bronchial epithelial cell	CL:0002328	82.48	gold quality
bronchus	UBERON:0002185	80.60	gold quality
oviduct epithelium	UBERON:0004804	75.72	gold quality
caput epididymis	UBERON:0004358	74.84	gold quality
corpus epididymis	UBERON:0004359	74.47	gold quality
anterior cingulate cortex	UBERON:0009835	74.47	gold quality
prefrontal cortex	UBERON:0000451	74.35	gold quality
left ovary	UBERON:0002119	73.98	gold quality
fallopian tube	UBERON:0003889	73.16	gold quality
colonic epithelium	UBERON:0000397	71.59	silver quality
ovary	UBERON:0000992	71.53	gold quality
pancreas	UBERON:0001264	71.40	gold quality
Brodmann (1909) area 23	UBERON:0013554	71.39	gold quality
Brodmann (1909) area 9	UBERON:0013540	71.27	gold quality
right atrium auricular region	UBERON:0006631	70.71	gold quality
neocortex	UBERON:0001950	69.97	gold quality
smooth muscle tissue	UBERON:0001135	69.87	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	69.85	gold quality
amygdala	UBERON:0001876	69.82	gold quality
middle temporal gyrus	UBERON:0002771	69.51	gold quality
frontal cortex	UBERON:0001870	69.38	gold quality
cardiac atrium	UBERON:0002081	69.36	gold quality
Ammon’s horn	UBERON:0001954	69.33	gold quality
endothelial cell	CL:0000115	68.68	gold quality
cerebral cortex	UBERON:0000956	68.66	gold quality
mucosa of paranasal sinus	UBERON:0005030	68.53	gold quality
right frontal lobe	UBERON:0002810	68.32	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	84.31
E-HCAD-25	yes	27.70
E-CURD-119	yes	26.62
E-MTAB-5061	yes	13.78
E-ANND-3	yes	4.46

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

94 targeting KCNMB2, 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-3646	100.00	73.56	5283
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-1-3P	99.93	72.35	1914

Literature-anchored findings (GeneRIF, showing 6)

• results reveal the molecular regions in the beta1 and beta2 subunits that determine their differential functional coupling with the pore-forming alpha-subunit (PMID:16446507)
• significance of inactivation in BK channels mediated by beta subunits arises not from inactivation, but from differences in the amplitude and duration of repolarizing currents arising from the beta-subunit-specific energetics of recovery from inactivation (PMID:17460083)
• reports that coexpression of beta2 subunit (KCNMB2) with hSlo can also modulate hSlo surface expression levels in HEK293T cells (PMID:17521822)
• Report beta subunit (KNMB1-4)-specific modulations of BK channel function by a Slo1 mutation associated with epilepsy and dyskinesia. (PMID:19204046)
• beta subunits of large-conductance calcium-dependent potassium channels modulate the interface between membrane-spanning and cytosolic domains. (PMID:23825428)
• IFN-gamma changed mRNA levels of the BK beta-modulatory proteins KCNMB2 (increased) and KCNMB4 (decreased) as well as leucine-rich repeat-containing protein (LRRC)26 (decreased). (PMID:24414257)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	s100p	ENSDARG00000001712
danio_rerio	kcnmb2a	ENSDARG00000006568
mus_musculus	Kcnmb2	ENSMUSG00000037610
rattus_norvegicus	Kcnmb2	ENSRNOG00000010094

Paralogs (3): KCNMB4 (ENSG00000135643), KCNMB1 (ENSG00000145936), KCNMB3 (ENSG00000171121)

Protein

Protein identifiers

Calcium-activated potassium channel subunit beta-2 — Q9Y691 (reviewed: Q9Y691)

Alternative names: BK channel subunit beta-2, Calcium-activated potassium channel, subfamily M subunit beta-2, Charybdotoxin receptor subunit beta-2, Hbeta3, K(VCA)beta-2, Maxi K channel subunit beta-2, Slo-beta-2

All UniProt accessions (4): E7EM81, E7ETM2, F8WE19, Q9Y691

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. Acts as a negative regulator that confers rapid and complete inactivation of KCNMA1 channel complex. May participate in KCNMA1 inactivation in chromaffin cells of the adrenal gland or in hippocampal CA1 neurons.

Subunit / interactions. Interacts with KCNMA1 tetramer. There are probably 4 molecules of KCMNB2 per KCNMA1 tetramer.

Subcellular location. Membrane.

Tissue specificity. Expressed in kidney, heart and brain. Highly expressed in ovary. Expressed at low level in other tissues.

Post-translational modifications. N-glycosylated.

Domain organisation. The ball and chain domain mediates the inactivation of KCNMA1. It occludes the conduction pathway of KCNMA1 channels, and comprises the pore-blocking ball domain (residues 1-17) and the chain domain (residues 20-45) linking it to the transmembrane segment. The ball domain is made up of a flexible N-terminus anchored at a well ordered loop-helix motif. The chain domain consists of a 4-turn helix with an unfolded linker at its C-terminus.

Similarity. Belongs to the KCNMB (TC 8.A.14.1) family. KCNMB2 subfamily.

RefSeq proteins (3): NP_001265840, NP_005823, NP_852006* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003930	K_chnl_Ca-activ_BK_bsu	Family
IPR015382	KCNMB2_ball_chain_dom	Domain
IPR037096	KCNMB2_ball/chain_dom_sf	Homologous_superfamily

Pfam: PF03185, PF09303

UniProt features (15 total): topological domain 3, glycosylation site 3, strand 2, transmembrane region 2, chain 1, mutagenesis site 1, helix 1, turn 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1JO6	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y691-F1	85.15	0.47

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 (3): 88, 96, 119

Mutagenesis-validated functional residues (1):

Position	Phenotype
2–4	abolishes inactivation of kcnma1 channel.

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: 171 (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, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_RESPONSE_TO_METAL_ION, GOBP_REGULATION_OF_ANATOMICAL_STRUCTURE_SIZE, BRN2_01, GOBP_REGULATION_OF_SYSTEM_PROCESS, GOBP_REGULATION_OF_VASOCONSTRICTION, GOBP_DETECTION_OF_STIMULUS, TGTTTAC_MIR30A5P_MIR30C_MIR30D_MIR30B_MIR30E5P

GO Biological Process (8): action potential (GO:0001508), detection of calcium ion (GO:0005513), potassium ion transport (GO:0006813), neuronal action potential (GO:0019228), regulation of vasoconstriction (GO:0019229), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220), potassium ion transmembrane transport (GO:0071805)

GO Molecular Function (5): ion channel inhibitor activity (GO:0008200), calcium-activated potassium channel activity (GO:0015269), potassium channel regulator activity (GO:0015459), potassium channel activity (GO:0005267), protein binding (GO:0005515)

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
ion channel regulator activity	2
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
vasoconstriction	1
blood vessel diameter maintenance	1
regulation of blood circulation	1
transport	1
monoatomic ion transport	1
transmembrane transport	1
potassium ion transport	1
monoatomic cation transmembrane transport	1
monoatomic ion channel activity	1
channel inhibitor activity	1
transmembrane transporter binding	1
calcium-activated cation channel activity	1
monoatomic cation channel activity	1
potassium ion transmembrane transporter activity	1
binding	1
membrane	1
cell periphery	1
potassium channel complex	1
plasma membrane protein complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

268 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCNMB2	KCNMA1	Q12791	620
KCNMB2	BHLHE23	Q8NDY6	571
KCNMB2	TMEM106B	Q9NUM4	399
KCNMB2	LRRC26	Q2I0M4	391
KCNMB2	KCNMB4	Q86W47	382
KCNMB2	KCNN1	Q92952	366
KCNMB2	ABCC9	O60706	358
KCNMB2	ADRA1D	P25100	354
KCNMB2	KCNN3	Q9UGI6	341
KCNMB2	RPP21	Q9H633	312
KCNMB2	KCNAB1	Q14722	311
KCNMB2	KCNMB1	P78475	308
KCNMB2	IGBP1	P78318	308
KCNMB2	MRPS24	P82668	293
KCNMB2	LRRC52	Q8N7C0	292

IntAct

9 interactions, top by confidence:

A	B	Type	Score
KCNMB2	WFS1	psi-mi:“MI:0915”(physical association)	0.560
HTT	KCNMB2	psi-mi:“MI:0915”(physical association)	0.560
KCNMA1	KCNMB2	psi-mi:“MI:0915”(physical association)	0.400
KCNMB2	TK1	psi-mi:“MI:0914”(association)	0.350
KCNMB2	ATP1A3	psi-mi:“MI:0914”(association)	0.350

BioGRID (11): KCNMB2 (Proximity Label-MS), MSRA (Affinity Capture-MS), ANKRD13A (Affinity Capture-MS), ANKRD13D (Affinity Capture-MS), TK1 (Affinity Capture-MS), STARD3 (Affinity Capture-MS), TMEM160 (Affinity Capture-MS), UBE3C (Affinity Capture-MS), ATP1A3 (Affinity Capture-MS), KCNMB2 (Affinity Capture-RNA), APP (Reconstituted Complex)

ESM2 similar proteins: A6NFY4, A6QNT4, A7MBC7, D3Z291, D3ZEH5, O14524, P0C8N6, P50747, P51811, P60570, Q2HJ63, Q2HJB9, Q3TD49, Q49LS5, Q49LS8, Q5F383, Q5GH61, Q5JZQ8, Q5PQL3, Q5RDB4, Q5RJQ8, Q5XII8, Q5ZJY9, Q5ZKY0, Q60GF7, Q6AXN4, Q6AYS5, Q6ZQE4, Q7SYC7, Q80UF9, Q811Q0, Q8C561, Q8CB65, Q8CHQ0, Q8CIF6, Q8K2I9, Q8NFZ0, Q8TCT8, Q8VEC4, Q90YH8

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

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	27
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2428 predictions. Top by Δscore:

Variant	Effect	Δscore
3:178825587:GAAAT:G	acceptor_gain	1.0000
3:178825756:GAG:G	donor_gain	1.0000
3:178828176:A:AG	acceptor_gain	1.0000
3:178828177:G:GG	acceptor_gain	1.0000
3:178828177:GC:G	acceptor_gain	1.0000
3:178828177:GCGT:G	acceptor_gain	1.0000
3:178842651:A:AG	acceptor_gain	1.0000
3:178842652:G:GA	acceptor_gain	1.0000
3:178842652:GT:G	acceptor_gain	1.0000
3:178419372:TGAGG:T	donor_loss	0.9900
3:178419373:GAG:G	donor_gain	0.9900
3:178807461:AAAAG:A	donor_loss	0.9900
3:178807462:AAAG:A	donor_loss	0.9900
3:178807462:AAAGG:A	donor_loss	0.9900
3:178807463:AAG:A	donor_loss	0.9900
3:178807463:AAGGT:A	donor_loss	0.9900
3:178807465:GGTAA:G	donor_loss	0.9900
3:178807466:G:GA	donor_loss	0.9900
3:178807467:T:G	donor_loss	0.9900
3:178825587:GAA:G	acceptor_gain	0.9900
3:178825754:CAGAG:C	donor_loss	0.9900
3:178825755:AGAG:A	donor_loss	0.9900
3:178825757:AG:A	donor_loss	0.9900
3:178825757:AGG:A	donor_loss	0.9900
3:178825758:GGTA:G	donor_loss	0.9900
3:178825758:GGTAA:G	donor_loss	0.9900
3:178825759:G:GC	donor_loss	0.9900
3:178825760:T:A	donor_loss	0.9900
3:178825760:T:C	donor_loss	0.9900
3:178828176:AGC:A	acceptor_gain	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000015562 (3:178671119 C>A), RS1000020575 (3:178742058 T>G), RS1000024062 (3:178823722 G>A), RS1000030388 (3:178729251 C>A), RS1000043375 (3:178838377 C>T), RS1000047890 (3:178540498 C>T), RS1000064563 (3:178625295 G>A), RS1000066671 (3:178559319 C>G,T), RS1000088302 (3:178647453 C>A), RS1000095371 (3:178625427 C>G,T), RS1000098996 (3:178735443 T>C), RS1000124716 (3:178794671 C>T), RS1000126965 (3:178664822 T>C), RS1000139572 (3:178823940 T>C), RS1000155623 (3:178695002 G>A)

Disease associations

OMIM: gene MIM:605214 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST000464_3	Acute lymphoblastic leukemia (childhood)	6.000000e-06
GCST001567_5	Bipolar disorder and schizophrenia	1.000000e-06
GCST001806_4	Corneal structure	1.000000e-08
GCST002337_105	Amyotrophic lateral sclerosis (sporadic)	9.000000e-07
GCST002589_5	Hippocampal sclerosis	7.000000e-08
GCST003989_37	Chin dimples	7.000000e-11
GCST004049_28	Cough in response to angiotensin-converting enzyme inhibitor drugs	8.000000e-07
GCST004719_5	Left ventricular obstructive tract defect (inherited effect)	6.000000e-06
GCST006428_2	Suicide attempts	9.000000e-07
GCST010294_1	Response to lamotrigine in genetic generalized epilepsy	9.000000e-07

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004345	corneal topography
EFO:0005325	response to angiotensin-converting enzyme inhibitor
EFO:0004321	attempted suicide

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

14 total (human), top 14 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol F	decreases methylation, increases expression	2
bisphenol A	decreases methylation	1
aflatoxin B2	increases methylation	1
CGP 52608	affects binding, increases reaction	1
bisphenol S	increases methylation	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Curcumin	decreases expression	1
Progesterone	decreases expression	1
Rotenone	increases expression	1
Tobacco Smoke Pollution	affects expression	1
Valproic Acid	increases expression	1
Cyclosporine	decreases methylation	1
Aflatoxin B1	increases methylation	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

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