title: Molecular mechanism underlying β1 regulation in voltage- and calcium-activated potassium (BK) channels.
abstract: Being activated by depolarizing voltages and increases in cytoplasmic Ca(2+), voltage- and calcium-activated potassium (BK) channels and their modulatory β-subunits are able to dampen or stop excitatory stimuli in a wide range of cellular types, including both neuronal and nonneuronal tissues. Minimal alterations in BK channel function may contribute to the pathophysiology of several diseases, including hypertension, asthma, cancer, epilepsy, and diabetes. Several gating processes, allosterically coupled to each other, control BK channel activity and are potential targets for regulation by auxiliary β-subunits that are expressed together with the α (BK)-subunit in almost every tissue type where they are found. By measuring gating currents in BK channels coexpressed with chimeras between β1 and β3 or β2 auxiliary subunits, we were able to identify that the cytoplasmic regions of β1 are responsible for the modulation of the voltage sensors. In addition, we narrowed down the structural determinants to the N terminus of β1, which contains two lysine residues (i.e., K3 and K4), which upon substitution virtually abolished the effects of β1 on charge movement. The mechanism by which K3 and K4 stabilize the voltage sensor is not electrostatic but specific, and the α (BK)-residues involved remain to be identified. This is the first report, to our knowledge, where the regulatory effects of the β1-subunit have been clearly assigned to a particular segment, with two pivotal amino acids being responsible for this modulation.
authors.affiliation: Centro Interdisciplinario de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2366103, Chile; and.
authors.forename: Karen
authors.initials: K
authors.lastname: Castillo
authors.affiliation: Centro Interdisciplinario de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2366103, Chile; and.
authors.forename: Gustavo F
authors.initials: GF
authors.lastname: Contreras
authors.affiliation: Centro Interdisciplinario de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2366103, Chile; and.
authors.forename: Amaury
authors.initials: A
authors.lastname: Pupo
authors.affiliation: Departmento de Nutricion y Bioquimica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogota DC 110111, Colombia.
authors.forename: Yolima P
authors.initials: YP
authors.lastname: Torres
authors.affiliation: Centro Interdisciplinario de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2366103, Chile; and.
authors.forename: Alan
authors.initials: A
authors.lastname: Neely
authors.affiliation: Centro Interdisciplinario de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2366103, Chile; and carlos.gonzalezl@uv.cl ramon.latorre@uv.cl.
authors.forename: Carlos
authors.initials: C
authors.lastname: González
authors.affiliation: Centro Interdisciplinario de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2366103, Chile; and carlos.gonzalezl@uv.cl ramon.latorre@uv.cl.
authors.forename: Ramon
authors.initials: R
authors.lastname: Latorre
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002118:Calcium / Q000378:metabolism*; D005260:Female; D006801:Humans; D015640:Ion Channel Gating / Q000235:genetics / Q000502:physiology*; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D008239:Lysine / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D008564:Membrane Potentials / Q000235:genetics / Q000502:physiology; D008958:Models, Molecular; D009154:Mutation; D009865:Oocytes / Q000378:metabolism / Q000502:physiology; D011188:Potassium / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: C531905:KCNMB1 protein, human; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits; D021122:Protein Subunits; D011993:Recombinant Fusion Proteins; D008239:Lysine; D011188:Potassium; D002118:Calcium
keywords: BK beta-subunits; BK channels; gating currents; voltage sensor
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