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Molecular mechanism underlying β1 regulation in voltage- and calcium-activated potassium (BK) channels

Significance β-Subunits (β1–β4) play a critical role in defining the properties of the voltage- and calcium-activated potassium (BK) channel, which in turn determines the physiological role that this channel can perform in different tissues. In particular, the β1-subunit causes an increase in the apparent BK Ca2+ sensitivity due to a stabilization of the voltage sensor in the active configuration. We investigated the molecular details of such voltage-sensor stabilization by mutagenesis and gating current measurements. Mixing regions of β1 and β3 made it possible to identify the N terminus, in particular the third and fourth lysine residues, as the structural element necessary to recover the full effect of β1 on the voltage sensor. Being activated by depolarizing voltages and increases in cytoplasmic Ca2+, 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.