Alternative titles; symbols
HGNC Approved Gene Symbol: KCNMB1
Cytogenetic location: 5q35.1 Genomic coordinates (GRCh38): 5:170,374,671-170,389,367 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q35.1 | {Hypertension, diastolic, resistance to} | 608622 | Autosomal dominant | 3 |
Large conductance, voltage- and calcium-sensitive potassium (MaxiK) channels are fundamental in the control of smooth muscle tone and neuronal excitability. MaxiK channels can be formed by 2 subunits: the pore-forming alpha subunit (SLO; 600150) and the modulatory beta subunit. MaxiK channels are sensitive to external application of several peptidyl toxins, such as charybdotoxin (ChTX), which bind with high affinity to a receptor site located in the external vestibule of the channel and prevent potassium flux by physical occlusion of the pore. Knaus et al. (1994) demonstrated that ChTX is specifically bound to the 31-kD beta subunit of the bovine tracheal smooth muscle MaxiK channel. They cloned cDNAs encoding the bovine beta subunit and found that the predicted protein contains 2 putative transmembrane domains. Under nondenaturing conditions, antibodies against the beta subunit immunoprecipitated both the alpha and beta subunits of the channel, demonstrating that, in vivo, the MaxiK channel exists as a multimer containing both alpha and beta subunits. Knaus et al. (1994) noted that the beta subunit must be in close proximity to the pore since ChTX, which blocks the pore on the alpha subunit, is covalently incorporated into the beta subunit.
Using the sequence of the bovine beta subunit, both Tseng-Crank et al. (1996) and Meera et al. (1996) cloned cDNAs encoding the human beta subunit. By Northern blot analysis, Tseng-Crank et al. (1996) found that the beta-subunit gene, which they called human SLO-beta, is widely expressed as a 1.4-kb transcript throughout human tissues. The highest level of expression was observed in aorta. Coexpression of the SLO-alpha and -beta subunits in Xenopus oocytes or mammalian cells gave rise to calcium-activated potassium currents with a pronounced increase in calcium and/or voltage sensitivity. Meera et al. (1996) reported that the concentration of intracellular calcium controls the functional coupling between beta and alpha subunits of the MaxiK channel complex, switching the alpha subunit from a calcium-independent to a calcium-dependent mode and from a beta subunit dull interaction to a beta subunit-activated mode. The functional switch develops at concentrations of calcium that occur during cellular excitation, providing the molecular basis for how MaxiK channels regulate smooth muscle excitability and neurotransmitter release.
Jiang et al. (1999) demonstrated that the mouse Kcnmb1 and human KCNMB1 beta subunit genes each contain 4 exons and span 9 kb and 11 kb of their respective genomes. The exon-intron junctions are highly conserved between human and mouse. The authors reported that mouse, rat, canine, bovine, and human MaxiK beta subunits each contain 191 amino acids, 71% of which are identical in all species.
By somatic cell hybrid and FISH analyses, Tseng-Crank et al. (1996) mapped the KCNMB1 gene to chromosome 5q34.
Calcium regulation of gene expression is critical for the long lasting activity-dependent changes in cellular electrical properties that underlie important physiologic functions such as learning and memory. Cellular electrical properties are diversified through the extensive alternative splicing of ion channel pre-mRNAs. The STREX exon of Slo confers higher calcium sensitivity on the channel. Xie and Black (2001) demonstrated that the depolarization of rat pituitary cells represses splicing of the STREX exon in BK potassium channel transcripts through the activation of calcium/calmodulin-dependent protein kinases. Overexpressing constitutively active CAMK4 (114080), but not CAMK1 (604998) or CAMK2 (114078), specifically decreases STREX inclusion in the mRNA. This decrease is prevented by mutations in particular RNA repressor sequences. Transferring 54 nucleotides from the 3-prime splice site upstream of STREX to a heterologous gene is sufficient to confer CAMK4 repression on an otherwise constitutive exon. Xie and Black (2001) concluded that their experiments define a CAMK4-responsive RNA element (CaRRE), which mediates the alternative splicing of ion channel pre-mRNAs. The CaRRE presents a unique molecular target for inducing long-term adaptive changes in cellular electrical properties. It also provides a model system for dissecting the effect of signal transduction pathways on alternative splicing.
Piskorowski and Aldrich (2002) showed that BK-calcium channels that lack the whole intracellular C terminus retain wildtype calcium sensitivity. They suggested that the intracellular C terminus, including the 'calcium bowl' and the RCK domain, is not necessary for the calcium-activated opening of these channels.
Neutrophil leukocytes have a pivotal function in innate immunity. The lethal blow is delivered to microbes by reactive oxygen species and halogens, products of the NADPH oxidase, whose impairment causes immunodeficiency. However, the microbes might be killed by proteases, activated by the oxidase through the generation of a hypertonic, potassium-rich and alkaline environment in the phagocytic vacuole (Reeves et al., 2002).
Fernandez-Fernandez et al. (2004) directly sequenced the exons encoding the KCNMB1 gene in 11 severely hypertensive and 12 strictly normotensive individuals and identified a 352G-A transition in the third exon (603951.0001), corresponding to a glu65-to-lys (E65K) substitution in the protein. The mutation resulted in a gain of function of the channel and was associated with low prevalence of moderate and severe diastolic hypertension. BK-beta-1(E65K) channels showed increased Ca(2+) sensitivity compared to wildtype channels, without changes in channel kinetics. Fernandez-Fernandez et al. (2004) concluded that the BK-beta-1(E65K) channel may offer a more efficient negative-feedback effect on vascular smooth muscle contractility, consistent with a protective effect of the K allele against the severity of diastolic hypertension (see 608622).
For a discussion of a possible association between variation in the KCNMB1 gene and severity of asthma in African American males, see 600807.
Small arteries exhibit tone, a partially contracted state that is an important determinant of blood pressure. In arterial smooth muscle cells, intracellular calcium paradoxically controls both contraction and relaxation. Calcium-dependent relaxation is mediated by local calcium release from the sarcoplasmic reticulum. These 'calcium sparks' activate calcium-dependent potassium (BK) channels composed of alpha- and beta-1 subunits. Brenner et al. (2000) showed that targeted deletion of the gene for the beta-1 subunit leads to a decrease in the calcium sensitivity of BK channels, a reduction in functional coupling of calcium sparks to BK channel activation, and increases in arterial tone and blood pressure. The beta-1 subunit of the BK channel, by tuning the channel's calcium sensitivity, is a key molecular component in translating calcium signals to the central physiologic function of vasoregulation.
The article by Ahluwalia et al. (2004) in which a series of electrophysiologic experiments purportedly demonstrated that microbial killing and digestion were abolished when the BK channel was blocked was retracted by the authors (with the exception of Jatinder Ahluwalia) after 2 reports of an inability to reproduce the results.
By direct sequencing of the exons encoding the KCNMB1 gene in 11 severely hypertensive and 12 strictly normotensive individuals, Fernandez-Fernandez et al. (2004) identified a 352G-A transition in the third exon, resulting in a glu65-to-lys (E65K) substitution. They screened a population sample of 3,876 randomly selected participants for this mutation and found genotype frequencies of 78.4% for EE homozygotes, 20% for EK heterozygotes, and 1.6% for KK homozygotes. The frequency of the E65K mutation (KK + KE) decreased with increasing diastolic blood pressure values, from 21.6% in the normotensive group to 3.2% in the severely hypertensive group, consistent with a protective effect of the K allele against the severity of diastolic hypertension (608622).
In 101 Spanish nuclear families consisting of offspring with ischemic heart disease who were younger than 55 years and both parents, Via et al. (2005) did not detect any association between the E65K polymorphism and ischemic heart disease.
Ahluwalia, J., Tinker, A., Clapp, L. H., Duchen, M. R., Abramov, A. Y., Pope, S., Nobles, M., Segal, A. W. The large-conductance Ca(2+)-activated K+ channel is essential for innate immunity. Nature 427: 853-858, 2004. Note: Retraction: Nature 468: 122 only, 2010. [PubMed: 14985765] [Full Text: https://doi.org/10.1038/nature02356]
Brenner, R., Perez, G. J., Bonev, A. D., Eckman, D. M., Kosek, J. C., Wiler, S. W., Patterson, A. J., Nelson, M. T., Aldrich, R. W. Vasoregulation by the beta-1 subunit of the calcium-activated potassium channel. Nature 407: 870-876, 2000. [PubMed: 11057658] [Full Text: https://doi.org/10.1038/35038011]
Fernandez-Fernandez, J. M., Tomas, M., Vazquez, E., Orio, P., Latorre, R., Senti, M., Marrugat, J., Valverde, M. A. Gain-of-function mutation in the KCNMB1 potassium channel subunit is associated with low prevalence of diastolic hypertension. J. Clin. Invest. 113: 1032-1039, 2004. [PubMed: 15057310] [Full Text: https://doi.org/10.1172/JCI20347]
Jiang, Z., Wallner, M., Meera, P., Toro, L. Human and rodent MaxiK channel beta-subunit genes: cloning and characterization. Genomics 55: 57-67, 1999. [PubMed: 9888999] [Full Text: https://doi.org/10.1006/geno.1998.5627]
Knaus, H.-G., Folander, K., Garcia-Calvo, M., Garcia, M. L., Kaczorowski, G. J., Smith, M., Swanson, R. Primary sequence and immunological characterization of beta-subunit of high conductance Ca(2+)-activated K+ channel from smooth muscle. J. Biol. Chem. 269: 17274-17278, 1994. [PubMed: 8006036]
Meera, P., Wallner, M., Jiang, Z., Toro, L. A calcium switch for the functional coupling between alpha (hslo) and beta subunits (K(V), Ca-beta) of maxi K channels. FEBS Lett. 382: 84-88, 1996. Note: Erratum: FEBS Lett. 385: 127-128, 1996. [PubMed: 8612769] [Full Text: https://doi.org/10.1016/0014-5793(96)00151-2]
Piskorowski, R., Aldrich, R. W. Calcium activation of BK(Ca) potassium channels lacking the calcium bowl and RCK domains. Nature 420: 499-502, 2002. [PubMed: 12466841] [Full Text: https://doi.org/10.1038/nature01199]
Reeves, E. P., Lu, H., Jacobs, H. L., Messina, C. G. M., Bolsover, S., Gabella, G., Potma, E. O., Warley, A., Roes, J., Segal, A. W. Killing activity of neutrophils is mediated through activation of proteases by K+ flux. Nature 416: 291-297, 2002. [PubMed: 11907569] [Full Text: https://doi.org/10.1038/416291a]
Tseng-Crank, J., Godinot, N., Johansen, T. E., Ahring, P. K., Strobaek, D., Mertz, R., Foster, C. D., Olesen, S.-P., Reinhart, P. H. Cloning, expression, and distribution of a Ca(2+)-activated K+ channel beta-subunit from human brain. Proc. Nat. Acad. Sci. 93: 9200-9205, 1996. [PubMed: 8799178] [Full Text: https://doi.org/10.1073/pnas.93.17.9200]
Via, M., Valveny, N., Lopez-Alomar, A., Athanasiadis, G., Pinto, X., Domingo, E., Esteban, E., Gonzalez-Perez, E., Moral, P. E65 K (sic) polymorphism in KCNMB1 gene is not associated with ischaemic heart disease in Spanish patients. J. Hum. Genet. 50: 604-606, 2005. [PubMed: 16155733] [Full Text: https://doi.org/10.1007/s10038-005-0298-9]
Xie, J., Black, D. L. A CaMK IV responsive RNA element mediates depolarization-induced alternative splicing of ion channels. Nature 410: 936-439, 2001. [PubMed: 11309619] [Full Text: https://doi.org/10.1038/35073593]