Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 15, Pages 4809-4814Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1504378112
Keywords
BK channels; gating currents; voltage sensor; BK beta-subunits
Categories
Funding
- FONDECYT [1110430, 1120802, 1120864]
- ANILLO Grant [ACT1104]
- Cooperation Grant Chile-Uruguay [130006]
- CONICYT
- Millennium Scientific Initiative of the Chilean Ministry of Economy, Development and Tourism
- [AT-24110157]
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Being activated by depolarizing voltages and increases in cytoplasmic Ca2+, voltage- and calcium-activated potassium (BK) channels and their modulatory beta-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 beta-subunits that are expressed together with the alpha (BK)-subunit in almost every tissue type where they are found. By measuring gating currents in BK channels coexpressed with chimeras between beta 1 and beta 3 or beta 2 auxiliary subunits, we were able to identify that the cytoplasmic regions of beta 1 are responsible for the modulation of the voltage sensors. In addition, we narrowed down the structural determinants to the N terminus of beta 1, which contains two lysine residues (i.e., K3 and K4), which upon substitution virtually abolished the effects of beta 1 on charge movement. The mechanism by which K3 and K4 stabilize the voltage sensor is not electrostatic but specific, and the alpha (BK)-residues involved remain to be identified. This is the first report, to our knowledge, where the regulatory effects of the beta 1-subunit have been clearly assigned to a particular segment, with two pivotal amino acids being responsible for this modulation.
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