The Membrane Cholesterol Modulates the Interaction Between 17-βEstradiol and the BK Channel

Abstract

BK channels are composed by the pore forming α subunit and, in some tissues, is associated with different accessory β subunits. These proteins modify the biophysical properties of the channel, amplifying the range of BK channel activation according to the physiological context. In the vascular cells, the pore forming BKα subunit is expressed with the β1 subunit, where they play an essential role in the modulation of arterial tone and blood pressure. In eukaryotes, cholesterol is a structural lipid of the cellular membrane. Changes in the ratio of cholesterol content in the plasma membrane (PM) regulates the BK channel activation altering its open probability, and hence, vascular contraction. It has been shown that the estrogen 17β-Estradiol (E2) causes a vasodilator effect in vascular cells, inducing a leftward shift in the V0.5 of the GV curve. Here, we evaluate whether changes in the membrane cholesterol concentration modify the effect that E2 induces on the BKα/β1 channel activity. Using binding and electrophysiology assays after cholesterol depletion or enrichment, we show that the cholesterol enrichment significantly decreases the expression of the α subunit, while cholesterol depletion increased the expression of that α subunit. Additionally, we demonstrated that changes in the membrane cholesterol cause the loss of the modulatory effect of E2 on the BKα/β1 channel activity, without affecting the E2 binding to the complex. Our data suggest that changes in membrane cholesterol content could affect channel properties related to the E2 effect on BKα/β1 channel activity. Finally, the results suggest that an optimal membrane cholesterol content is essential for the activation of BK channels through the β1 subunit.

Hypoxic Regulation of the Large-Conductance, Calcium and Voltage-Activated Potassium Channel, BK

“…Recently, we reported that changes in cholesterol concentration reduces the effects of 17β-Estradiol (E2) in the BK channel activity. However, that effect was not induced by changes in the expression of the BK β1 subunit ( Granados et al, 2021 ). Considering that hypoxia reduces the membrane cholesterol concentration, we suggested that reported changes in the modulation of Tamoxifen and E2 after hypoxia could also be related to changes in membrane cholesterol concentration.…”