Gain-of-function mutation in the KCNMB1 potassium channel subunit is associated with low prevalence of diastolic hypertension

Fernández‐Fernández, José M.; Tomàs, Marta; Vázquez, Esther; Orio, Patricio; Latorre, Ramón; Sentı́, Mariano; Marrugat, Jaume; Valverde, Miguel A.

doi:10.1172/jci200420347

Cited by 157 publications

(55 citation statements)

References 44 publications

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“…Careful scrutiny of genomic associations and polymorphisms in candidate genes will be required. Several hypertensionassociated loci that have been identified in genome-wide linkage studies contain candidate genes that we and others are currently exploring, including the Rho kinases (ROCK1, located at chromosome18q11.2; and ROCK2, at 2p24) (29,30) and the BK channel β subunit (on 5q34) (31,32 The hypothalamic-pituitary-adrenal axis (a major component of the stress system) and the immune system contribute to the maintenance of homeostasis at rest and during stress. Because of their essential roles for the survival of self and species, the activities of these systems have evolutionarily developed in parallel and are intertwined at many levels.…”

Section: Figurementioning

confidence: 99%

In hypertension, the kidney is not always the heart of the matter

Mendelsohn¹

2005

J. Clin. Invest.

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Blood pressure abnormalities are thought to originate from intrinsic changes in the kidney, a concept that has been largely unchallenged for more than 4 decades. However, recent molecular, cellular, and transgenic mouse studies support an alternative hypothesis: primary abnormalities in vascular cell function can also directly cause abnormalities of blood pressure. In this issue of the JCI, Crowley and coworkers describe the application of an elegant cross-renal transplant model to type 1A angiotensin (AT1A) receptor–deficient mice and their wild-type littermates to explore the relative contributions of renal and extrarenal tissues to the low blood pressure seen in the AT1A receptor–deficient animals. Their studies further support the emerging paradigm that primary abnormalities of the vasculature can make unique, nonredundant contributions to blood pressure regulation; the findings have potentially important implications for the ways we diagnose and treat blood pressure diseases in humans

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Section: Figurementioning

confidence: 99%

In hypertension, the kidney is not always the heart of the matter

Mendelsohn¹

2005

J. Clin. Invest.

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“…In this issue of the JCI, a report based on the results of a large genetic epidemiological study (3,876 participants) by Fernández-Fernández et al describes a new single nucleotide substitution (G352A) in the third exon of the KCNMB1 gene (27). The resulting mutant protein (β 1E65K ) contains a glutamic acid to lysine substitution at position 65 in the β 1 subunit.…”

Section: Association Between Genetic Variants Of the β β 1 Subunit (Kmentioning

confidence: 99%

“…To test this hypothesis, the investigators examined the effects of β 1E65K on the Ca 2+ -and voltage-activation of human BK channel α subunit (hSlo1), expressed in HEK-293 cells (27). As has been previously shown, expression of the wild-type β 1 subunit increased the apparent Ca 2+ -and voltagesensitivity of the pore-forming α subunit.…”

Section: Association Between Genetic Variants Of the β β 1 Subunit (Kmentioning

confidence: 99%

“…The study by Fernán-dez-Fernández et al (27) provides an exciting complementary view, demonstrating that a gain-of-function BK channel β 1 subunit variant exerts a protective effect against diastolic hypertension in humans. The combined use of human genetic epidemiological studies and functional studies on exogenously expressed channels in vitro has established the basic mechanism that connects BK channel function with a form of human hypertension.…”

Section: Future Directionsmentioning

confidence: 99%

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The β1 subunit of the Ca2+-sensitive K+ channel protects against hypertension

Nelson¹,

Bonev²

2004

J. Clin. Invest.

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Proposed role for the β1E65K subunit, resulting from a single point mutation in the β1 subunit and leading to a gain-of-function of the BK channel and vasodilation. (A) The BK channels in smooth muscle are composed of α pore-forming subunits and β1 subunits. Local Ca 2+ release (Ca 2+ sparks) through a cluster of ryanodine receptors (RyRs) in the sarcoplasmic reticulum (SR) membrane activates nearby BK channels leading to membrane potential hyperpolarization, decreased influx of Ca 2+ through voltage-dependent Ca 2+ channels (VDCCs), and less contraction. β1 subunits play a crucial role in the Ca 2+ spark-BK channel negative feedback loop, since they increase the Ca 2+ -sensitivity of the pore-forming α subunit of the BK channel. (B) The mutant form of the β1 subunit, the β1E65K subunit, which reflects a single amino acid substitution, has an even higher efficacy in enhancing the Ca 2+ -sensitivity of BK channels resulting in their gain-of-function. Hence, the mutant β1E65K subunit enhances the role of the Ca 2+ spark-BK channel negative feedback mechanism in limiting vasoconstriction and effectively provides protection against diastolic hypertension. commentaries

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“…In VSM, a single amino acid polymorphism in the BKβ 1 subunit (i.e., E65K) is reported to have a gain-of-function effect on BKs channel activation and has been associated with lower systolic and diastolic blood pressures and a decreased prevalence of diabetic hypertension in humans (Fernández-Fernández et al, 2004; Nielsen et al, 2008). In contrast, BKβ 1 subunit expression is decreased in some forms of genetic hypertension (Amberg and Santana, 2003).…”

Section: Role Of Bk Channels In Smooth Muscle Function and Diseasementioning

confidence: 99%

The regulation of BK channel activity by pre- and post-translational modifications

Kyle

Braun

2014

Front. Physiol.

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Large conductance, Ca2+-activated K+ (BK) channels represent an important pathway for the outward flux of K+ ions from the intracellular compartment in response to membrane depolarization, and/or an elevation in cytosolic free [Ca2+]. They are functionally expressed in a range of mammalian tissues (e.g., nerve and smooth muscles), where they can either enhance or dampen membrane excitability. The diversity of BK channel activity results from the considerable alternative mRNA splicing and post-translational modification (e.g., phosphorylation) of key domains within the pore-forming α subunit of the channel complex. Most of these modifications are regulated by distinct upstream cell signaling pathways that influence the structure and/or gating properties of the holo-channel and ultimately, cellular function. The channel complex may also contain auxiliary subunits that further affect channel gating and behavior, often in a tissue-specific manner. Recent studies in human and animal models have provided strong evidence that abnormal BK channel expression/function contributes to a range of pathologies in nerve and smooth muscle. By targeting the upstream regulatory events modulating BK channel behavior, it may be possible to therapeutically intervene and alter BK channel expression/function in a beneficial manner.

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Gain-of-function mutation in the KCNMB1 potassium channel subunit is associated with low prevalence of diastolic hypertension

Abstract: Nonstandard abbreviations used: large conductance, Ca 2+ -dependent K + (BK); conductance (G); diastolic blood pressure (DBP); odds ratio (OR); open probability (PO).

Cited by 157 publications

References 44 publications

In hypertension, the kidney is not always the heart of the matter

In hypertension, the kidney is not always the heart of the matter

The β1 subunit of the Ca2+-sensitive K+ channel protects against hypertension

The regulation of BK channel activity by pre- and post-translational modifications

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