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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Figure 5

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Effect of β1E65K on BK channel activation and deactivation kinetics. (A)...
Effect of β1E65K on BK channel activation and deactivation kinetics. (A) Current traces normalized to peak current were obtained with a pulse from 0 mV to +200 mV in the presence of 1.6 μM Ca2+. (B) Activation-time constants (at 1.6 μM Ca2+) were fitted with a single exponential function and plotted versus the pulse potential for α (open triangles, n = 4), α+β1WT (open circles, n = 13), α+β1E65K (filled circles, n = 15), and α+β1WT+β1E65K currents (open squares, n = 6). (C) Plot of activation-time constants versus Ca2+ concentrations measured with a pulse to +200 mV. (D) Families of tail currents recorded at 1.6 μM Ca2+ under the four conditions. (E and F) Deactivation-time constants were obtained by fitting of the tail currents with a single exponential function and plotted versus the pulse potential (E) or versus the Ca2+ concentration at –80 mV (F).