Key result
In β4-knockout neurons, Fostriecin increases BK current and speeds up activation, suggesting fast-gating BK channels lacking β4 increase neuronal excitability in response to reduced phosphatase activity.
The β4 subunit plays an important role in moderating neuronal firing frequency by opposing BK channel activation regardless of changes in phosphorylation status.
β4 loss may heighten excitability via phosphatase-sensitive BK channels in rodents; leaves open therapeutic targeting in human neuronal disorders.
Large-conductance voltage- and calcium-activated potassium (BK) channels are large-conductance calcium- and voltage-activated potassium channels critical for neuronal excitability. Some neurons express so called fast-gated, type I BK channels. Other neurons express BK channels assembled with the accessory β4 subunit conferring slow gating of type II BK channels. However, it is not clear how protein phosphorylation modulates these two distinct BK channel types. Using β4-knockout mice, we compared fast- or slow-gated BK channels in response to changes in phosphorylation status of hippocampus dentate gyrus granule neurons. We utilized the selective PP2A/PP4 phosphatase inhibitor Fostriecin to study changes in action potential shape and firing properties of the neurons. In β4-knockout neurons, Fostriecin increases BK current, speeds up BK channel activation and reduces action potential amplitudes. Fostriecin increases spiking during early components of an action potential train. In contrast, inhibition of BK channels through β4 in wild-type neurons or by the BK channel inhibitor Paxilline opposes Fostriecin effects. Voltage clamp recordings of neurons reveal that Fostriecin increases both calcium and BK currents. However, Fostriecin does not activate BK α channels in transfected HEK293 cells lacking calcium channels. In summary, these results suggest that fast-gating, type I BK channels lacking β4 can increase neuronal excitability in response to reduced phosphatase activity and activation of calcium channels. By opposing BK channel activation, the β4 subunit plays an important role in moderating firing frequency regardless of changes in phosphorylation status.
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Petřík et al. (2011) studied this question. Fostriecin and β4-knockout vs. Wild-type neurons or Paxilline was evaluated on Changes in action potential shape, firing properties, and BK current. In β4-knockout neurons, Fostriecin increases BK current and speeds up activation, suggesting fast-gating BK channels lacking β4 increase neuronal excitability in response to reduced phosphatase activity.
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