Voltage-dependent K⁺ channel acts as sex steroid sensor in endocrine cells of the human ovary

Molecular targets of rapid non-genomic steroid actions are not well known compared to those of the classical transcription pathway, but ion channels have recently been identified to be steroid-sensitive. Especially, in the ovary, the very organ producing high amounts of sex steroids, their rapid actions are not well examined. We now identified a yet unknown target for sex steroids, a voltage-dependent K⁺ channel (K_V4.2) that contributes to a transient outward K⁺ current (I_A) in human granulosa cells (GCs). Sex steroid hormones at concentrations typical for the ovary (1 μM) blocked K_V4.2 thereby attenuating I_A by about 25% within seconds. We also found both K_V4.2 (KCND2)mRNA and protein in endocrine cells of the human and rhesus macaque ovary, emphasizing the physiological relevance of this channel. Therefore, we propose a role as fast-responding steroid sensor for the K_V4.2 channel. The direct regulation of K⁺ channel activity by sex steroids might represent a yet unknown mechanism of rapid steroid action in close proximity to the site of steroid production in the primate ovary. Our data might also be important for K_V4 channels in the brain and the cardiovascular system where rapid steroid effects are discussed in the context of prevention of cell death.