Disease relevance of KCNMB1

• Gain-of-function mutation in the KCNMB1 potassium channel subunit is associated with low prevalence of diastolic hypertension [1].
• E65 K polymorphism in KCNMB1 gene is not associated with ischaemic heart disease in Spanish patients [2].
• Deletion of the Ca2+-activated potassium (BK) alpha-subunit but not the BKbeta1-subunit leads to progressive hearing loss [3].
• Patients with beta-thalassemia (Hbeta th) and sickle cell anemia (SCA) can be treated with bone marrow transplantation [4].

High impact information on KCNMB1

• The BK beta1-subunit, which is expressed in smooth muscle, increases the apparent Ca(2+) sensitivity (marked by a hyperpolarizing shift in the conductance-voltage relationship at a given Ca(2+) concentration), slows macroscopic activation and deactivation, and is required for channel activation by 17beta-estradiol [5].
• Analyzing the hearing function and cochlear phenotype of BK channel alpha-(BKalpha-/-) and beta1-subunit (BKbeta1-/-) knockout mice, we demonstrate normal hearing function and cochlear structure of BKbeta1-/- mice [3].
• The coexpression of hslo-beta mRNA together with hslo-alpha subunits in either Xenopus oocytes or stably transfected HEK 293 cells give rise to Ca(2+)-activated potassium currents with a much increased calcium and/or voltage sensitivity [6].
• The gene for this subunit is located on chromosome 5 at band q34 (hslo-beta) [6].
• DNA from three cell lines, digested with several restriction enzymes, produced a pattern providing evidence for the presence of circular H beta 1 molecules in the murine recipient cells [7].

Biological context of KCNMB1

• METHODS : We studied six single-nucleotide polymorphisms (SNPs) in KCNMB1 [8].
• Protective effect of the KCNMB1 E65K genetic polymorphism against diastolic hypertension in aging women and its relevance to cardiovascular risk [9].
• There is no evidence for alternative RNA splicing of this gene product. hslo-beta mRNA is abundantly expressed in smooth muscle, but expression levels are low in most other tissues, including brain [6].
• Phenotypic alteration of a human BK (hSlo) channel by hSlobeta subunit coexpression: changes in blocker sensitivity, activation/relaxation and inactivation kinetics, and protein kinase A modulation [10].
• A human homolog of the large-conductance calcium-activated potassium (BK) channel beta subunit (hSlobeta) was cloned, and its effects on a human BK channel (hSlo) phenotype are reported [10].

Anatomical context of KCNMB1

• Consistent with a tissue-specific expression of KCNMB1, regulated at the transcriptional level, beta-subunit transcripts are abundant in smooth muscle and heart, but scarce in lymphatic tissues, brain, and liver [11].
• Our studies revealed that BKbeta1 interacts with cytochrome c oxidase I (Cco1) in cardiac mitochondria, and that the activation of BK channels by 17beta-estradiol results in a significant increase in the survival rate of ventricular myocytes [12].
• These findings suggest that BKbeta1 may play an important role in the regulation of cell respiration in cardiac myocytes and be a target for the modulation by female gonadal hormones [12].
• Expression of BK beta1 in mesenteric arteries is closely correlated with BP in SHR [13].
• 5. In the prostatic vas deferens, halpha-CGRP, hbeta-CGRP and rat beta-CGRP (10(-10) - 3 x 10(-7) M) concentration-dependently inhibited twitch responses with about equal potency, while rat amylin (10(-8) - 10(-5) M) was around 10 fold less potent and the linear analogue [Cys(ACM2,7)] halpha-CGRP was at least 3000 fold weaker [14].

Associations of KCNMB1 with chemical compounds

• Internal dialysis of human embryonic kidney cells stably expressing CLCA1 with 500 nM Ca(2+) evoked a significantly larger current when the beta-subunit KCNMB1 was co-expressed [15].
• Thus our results argue that the variety of Slo-beta subunit coexpression patterns occurring in vivo expands the repertoire of Slo channel gating in yet another dimension not fully appreciated, rendering BK gating responsive to dynamic fluctuations in a multiple of steroid hormones [16].
• CONCLUSIONS: The deletion of BKbeta1 causes endothelial dysfunction by increasing O2- formation via increasing activity and expression of the vascular NADPH oxidase [17].
• By targeting a cysteine residue near the Ca(2+) bowl of the BK alpha subunit, H(2)O(2) virtually eliminates physiological activation of the channel, with an inhibitory potency comparable to a knockout of the auxiliary subunit BK beta 1 [18].
• There is one Cys residue in the single TM segment of beta-subunit (Hbeta) [19].

Other interactions of KCNMB1

• BKbeta4 slowed activation kinetics more significantly, led to a steeper apparent calcium sensitivity, and shifted the voltage range of BK current activation to more negative potentials than BKbeta1 [20].
• Association analysis between hypertension and CYBA, CLCNKB, and KCNMB1 functional polymorphisms in the Japanese population--the Suita Study [21].
• The significance of the CLCNKB/T481S and KCNMB1/E65K polymorphisms were not replicated in the present study [21].
• Other proton interactions were tentatively assigned to H beta 1 of His-44, H delta 2 of His-46 and to H beta 2 of His-44 [22].
• 4 Human alpha-CGRP8-37 (3 x 10(-7) - 3 x 10(-6) M) antagonized halpha-CGRP (pA2 6.9, Schild plot slope 1.2+/-0.1) and hbeta-CGRP (apparent pKB of 7.1+/-0.1 for halpha-CGRP8-37 10(-6) M) in the pulmonary artery [14].

Analytical, diagnostic and therapeutic context of KCNMB1

• Our large population-based genetic epidemiological study has identified a new single-nucleotide substitution (G352A) in the beta(1) gene (KCNMB1), corresponding to an E65K mutation in the protein [1].
• Both *OOH and O2*- adducts, with different 14N and Hbeta splittings, were detected simultaneously in some samples, for the first time in the spin trapping literature [23].

References