Regulation of STREX exon large conductance, calcium-activated potassium channels by the β4 accessory subunit

Large conductance (BK-type) calcium-activated potassium channels utilize alternative splicing and association with accessory β subunits to tailor BK channel properties to diverse cell types. Two important modulators of BK channel gating are the neuronal-specific beta4 accessory subunit (β4) and alternative splicing at the stress axis hormone-regulated exon (STREX). Individually, these modulators affect the gating properties of the BK channel as well as its response to phosphorylation. In this study, the combined functional consequences of STREX and the mouse β4 subunit on mouse BK channel biophysical properties were investigated in transfected HEK 293 cells. Surprisingly, we found that the combined effects of STREX and β4 are non-additive and even opposite for some properties. At high calcium, β4 and the STREX individually share properties that promote BK channel opening via slowing of deactivation. However, the combined effects are a speeding of deactivation and a decreased open probability. β4 also inhibits BK channel opening by a slowing of activation. This effect occurs across calcium concentrations in the absence of STREX, but predominates only at low calcium for STREX containing channels. BK channel responses to phosphorylation status are also altered by the combination of the β4 subunit and STREX. β4/STREX channels show a slowing of activation kinetics following dephosphorylation whereas β4 channels lacking STREX do not. In contrast, β4 confers a speeding of activation in response to cyclic AMP–dependent phosphorylation in channels lacking STREX, but not in channels containing STREX. These results indicate that the combination of the β4 subunit and STREX confers non-additive and unique properties to BK channels. Analysis of expression in brain slices suggests that STREX and β4 mRNA overlap expression in the dentate gyrus of the hippocampus and the cerebellar Purkinje cells, suggesting that these unique properties of BK channels may underlie BK channel gating in these cells.