Gain-of-function mutation in the KCNMB1 potassium channel subunit is associated with low prevalence of diastolic hypertension
José M. Fernández-Fernández, Marta Tomás, Esther Vázquez, Patricio Orio, Ramón Latorre, Mariano Sentí, Jaume Marrugat, Miguel A. Valverde
José M. Fernández-Fernández, Marta Tomás, Esther Vázquez, Patricio Orio, Ramón Latorre, Mariano Sentí, Jaume Marrugat, Miguel A. Valverde
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Article Cardiology

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

Abstract

Hypertension is the most prevalent risk factor for cardiovascular diseases, present in almost 30% of adults. A key element in the control of vascular tone is the large-conductance, Ca2+-dependent K+ (BK) channel. The BK channel in vascular smooth muscle is formed by an ion-conducting α subunit and a regulatory β1 subunit, which couples local increases in intracellular Ca2+ to augmented channel activity and vascular relaxation. Our large population-based genetic epidemiological study has identified a new single-nucleotide substitution (G352A) in the β1 gene (KCNMB1), corresponding to an E65K mutation in the protein. This mutation results in a gain of function of the channel and is associated with low prevalence of moderate and severe diastolic hypertension. BK-β1E65K channels showed increased Ca2+ sensitivity, compared with wild-type channels, without changes in channel kinetics. In conclusion, the BK-β1E65K channel might 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.

Authors

José M. Fernández-Fernández, Marta Tomás, Esther Vázquez, Patricio Orio, Ramón Latorre, Mariano Sentí, Jaume Marrugat, Miguel A. Valverde

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Plots of conductance versus voltage for BK channel currents at different...
Plots of conductance versus voltage for BK channel currents at different Ca2+ concentrations. BK channel currents were recorded from patches excised from cells expressing α (A), α+β1WT (B), α+β1E65K (C), and α+β1WT+β1E65K (D) channel subunits. Normalized conductance was obtained for each test potential from the peak tail current at –80 mV measured at 0 (circles), 100 nM (squares), 500 nM (triangles), and 10 μM (inverted triangles) Ca2+. Solid curves represent fits to the Boltzmann equation. The data at 0 and 100 nM Ca2+ were normalized using the value obtained at 500 nM as maximum tail current. To obtain an average G-V curve for each case, individual curves were displaced along the voltage axis by ΔV = (<V1/2> – V1/2) (where <V1/2> denotes the average V1/2 for each transfection group). The 300–360 resulting points were then reduced to 61 with the smoothing function of SigmaPlot (SPSS Inc., Richmond, California, USA).