Estradiol inhibition of voltage-activated and gonadotropin-releasing hormone-induced currents in mouse gonadotrophs

We report the first study of voltage-activated and GnRH-induced plasma membrane currents and their modulation by estradiol (E₂) in mouse gonadotrophs. In consideration of the pleiotropic effects of E₂ on gonadotrophin secretion and the relationship between plasma membrane electrical excitability and secretion, our objective was to determine the role of E ₂ in modulating gonadotroph plasma membrane currents. We measured total voltage-activated and GnRH-induced currents using the perforated-patch configuration of the patch-clamp technique, which preserves signaling pathways, including GnRH-induced Ca²⁺ oscillations. We show that female mouse gonadotrophs are similar to those from other species in that the voltage-activated net current response exhibits an inward fast activating current that is inhibited by tetrodotoxin, which is characteristic of a Na ⁺ current, and a larger magnitude outward current with a profile suggesting the presence of multiple K⁺ currents. Furthermore, in voltage-clamped mouse gonadotrophs, GnRH activates large amplitude current oscillations that are apamin sensitive and have a reversal potential of -90 mV, consistent with Ca²⁺-activated K⁺ currents. Significantly, E₂ pretreatment for 2-5 d decreased the density of both the peak outward voltage-activated current and the peak GnRH-induced current. The specific linkage between the observed E₂ effects on membrane currents and, ultimately, gonadotroph function remains to be established. However, because decreased K⁺ current density is associated with an increase in membrane electrical excitability, we postulate increased excitability is one of the modes of action of E₂ in sensitizing the gonadotroph to GnRH, an event central to the regulation of cyclic gonadotrophin secretion.