title: 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, Ca(2+)-dependent K(+) (BK) channel. The BK channel in vascular smooth muscle is formed by an ion-conducting alpha subunit and a regulatory beta(1) subunit, which couples local increases in intracellular Ca(2+) to augmented channel activity and vascular relaxation. 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. This mutation results in a gain of function of the channel and is associated with low prevalence of moderate and severe diastolic hypertension. BK-beta(1E65K) channels showed increased Ca(2+) sensitivity, compared with wild-type channels, without changes in channel kinetics. In conclusion, the BK-beta(1E65K) 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.affiliation: Unitat de Senyalització Cel.lular, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Fernández-Fernández
authors.forename: Marta
authors.initials: M
authors.lastname: Tomás
authors.forename: Esther
authors.initials: E
authors.lastname: Vázquez
authors.forename: Patricio
authors.initials: P
authors.lastname: Orio
authors.forename: Ramón
authors.initials: R
authors.lastname: Latorre
authors.forename: Mariano
authors.initials: M
authors.lastname: Sentí
authors.forename: Jaume
authors.initials: J
authors.lastname: Marrugat
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Valverde
mesh_terms: D000328:Adult; D000368:Aged; D002118:Calcium / Q000378:metabolism; D005260:Female; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism; D007700:Kinetics; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008297:Male; D008564:Membrane Potentials; D008875:Middle Aged; D008954:Models, Biological; D009154:Mutation; D018408:Patch-Clamp Techniques; D024681:Potassium Channels, Calcium-Activated / Q000235:genetics* / Q000378:metabolism
chemical_list: D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D051036:Large-Conductance Calcium-Activated Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D002118:Calcium