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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Fitting of the experimental data to an allosteric model of BK channel ga...
Fitting of the experimental data to an allosteric model of BK channel gating. (A and B) G-V plots for α+β1WT (A) and α+β1E65K (B) currents measured at 0 (circles), 100 nM (squares), 500 nM (triangles), and 10 μM (inverted triangles) Ca2+. Solid curves represent fits to Equation 1 (see Methods) with parameters restricted as described in the text. (C) G-V plots for α+β1WT (solid line) and α+β1E65K (dashed line) channels as predicted by the model. (D) V1/2-versus-Ca2+ plots obtained from the G-V curves presented in C. (E) Allosteric kinetic scheme proposed for the BK channel by Horrigan and Aldrich (33, 34). The C-O transition corresponds to the closed-open equilibrium where L = L0 exp(zL × V / kT). The R-A transition corresponds to the resting-active equilibrium of a single voltage sensor where J = J0 exp(zJ × V / kT). The X·Ca2+ transition is calcium binding to a single calcium sensor, with equilibrium constant K = [Ca2+] / Kd. These three equilibriums are related to each other by the allosteric factors C, D, and E, as shown. When there are n voltage sensors active, the C-O equilibrium constant is LDn. Conversely, when the channel is open, the R-A equilibrium constant is JD. The same applies for the allosteric factors C and E.