Figure 7

A model illustrating the concerted effect of EPHB6 and testosterone in regulating Ca²⁺ influx in adrenal gland chromaffin cells. In adrenal gland chromaffin cells, acetylcholine (ACh) stimulation of acetylcholine receptors (AChR) causes initial depolarization by allowing a small amount of Ca²⁺ influx plus a large amount of Na⁺ influx. The combined effect of both inward cation fluxes opens voltage-gated calcium channels for larger Ca²⁺ influx. BK channels are then activated by depolarization as well as by increased Ca²⁺ concentration, allowing K⁺ ions efflux, therein repolarizing the cells. As a consequence, voltage-gated calcium channels (VGCC) are shut down, terminating Ca²⁺ influx. Testosterone promotes the BK currents by direct binding with the BK channel, or by non-genomic signaling via its cell surface androgen receptors (AR) or via intracellular Src kinases. EPHB6 might interfere with the testosterone-BK association, or block the interaction between testosterone and AR, or suppress Src signaling. These 3 possible mechanisms are to be tested, and hence marked with question marks. As a consequence, the presence of EPHB6 suppresses the positive effect of testosterone on the BK currents. EPHB6 KO liberates this positive impact, leading to a larger K⁺ outflow. This results in earlier and faster repolarization, an earlier closure of voltage-gated calcium channels, and the subsequently reduced Ca²⁺ influx.