Differential Functional Contribution of BK Channel Subunits to Aldosterone-Induced Channel Activation in Vascular...

Calcium/voltage-activated potassium channels (BK) control smooth muscle (SM) tone and cerebral artery diameter. They include channel-forming α and regulatory β₁ subunits, the latter being highly expressed in SM. Both subunits participate in steroid-induced modification of BK activity: β₁ provides recognition for estradiol and cholanes, resulting in BK potentiation, whereas α suffices for BK inhibition by cholesterol or pregnenolone. Aldosterone can modify cerebral artery function independently of its effects outside the brain, yet BK involvement in aldosterone's cerebrovascular action and identification of channel subunits, possibly involved in steroid action, remains uninvestigated. Using microscale thermophoresis, we demonstrated that each subunit type presents two recognition sites for aldosterone: at 0.3 and ≥10 µM for α and at 0.3-1 µM and ≥100 µM for β₁. Next, we probed aldosterone on SM BK activity and diameter of middle cerebral artery (MCA) isolated from β₁ vs. wt mice. Data showed that β₁ leftward-shifted aldosterone-induced BK activation, rendering EC₅₀~3 μM and EC_MAX ≥ 10 μM, at which BK activity increased by 20%. At similar concentrations, aldosterone mildly yet significantly dilated MCA independently of circulating and endothelial factors. Lastly, aldosterone-induced MCA dilation was lost in β₁ mice. Therefore, β₁ enables BK activation and MCA dilation by low µM aldosterone.