Ovarian Steroids Stimulate Adenosine Triphosphate-Sensitive Potassium (KATP) Channel Subunit Gene Expression and Confer Responsiveness of the Gonadotropin-Releasing Hormone Pulse Generator to KATP Channel Modulation

Feb 9, 2008Endocrinology

Ovarian hormones increase potassium channel gene activity and make hormone pulse control sensitive to potassium channel changes

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Abstract

Blockade of K(ATP) channels in the hypothalamus increased LH pulse frequency in ovariectomized rats treated with E(2)+P.

K(ATP) channels are involved in regulating pulsatile GnRH secretion, as indicated by changes in LH secretion.
The K(ATP) channel blocker tolbutamide increased LH pulse frequency only in rats treated with E(2)+P.
Co-infusion of tolbutamide and the K(ATP) channel opener diazoxide blocked the effect of tolbutamide on LH frequency.
E(2)+P treatment increased Kir6.2 mRNA expression in the preoptic area, which was reversed by blocking progesterone receptors.
After prolonged treatment, Kir6.2 mRNA levels were further enhanced by E(2)+P in the preoptic area.

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The ATP-sensitive potassium (K(ATP)) channels couple intracellular metabolism to membrane potential. They are composed of Kir6.x and sulfonylurea receptor (SUR) subunits and are expressed in hypothalamic neurons that project to GnRH neurons. However, their roles in regulating GnRH secretion have not been determined. The present study first tested whether K(ATP) channels regulate pulsatile GnRH secretion, as indirectly reflected by pulsatile LH secretion. Ovariectomized rats received sc capsules containing oil, 17beta-estradiol (E(2)), progesterone (P), or E(2)+P at 24 h before blood sampling. Infusion of the K(ATP) channel blocker tolbutamide into the third ventricle resulted in increased LH pulse frequency in animals treated with E(2)+P but was without effect in all other groups. Coinfusion of tulbutamide and the K(ATP) channel opener diazoxide blocked this effect, whereas diazoxide alone suppressed LH. Effects of steroids on Kir6.2 and SUR1 mRNA expression were then evaluated. After 24hr treatment, E(2)+P produced a modest but significant increase in Kir6.2 expression in the preoptic area (POA), which was reversed by P receptor antagonism with RU486. Neither SUR1 in the POA nor both subunits in the mediobasal hypothalamus were altered by any steroid treatment. After 8 d treatment, Kir6.2 mRNA levels were again enhanced by E(2)+P but to a greater extent in the POA. Our findings demonstrate that 1) blockade of preoptic/hypothalamic K(ATP) channels produces an acceleration of the GnRH pulse generator in a steroid-dependent manner and 2) E(2)+P stimulate Kir6.2 gene expression in the POA. These observations are consistent with the hypothesis that the negative feedback actions of ovarian steroids on the GnRH pulse generator are mediated, in part, by their ability to up-regulate K(ATP) channel subunit expression in the POA.

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Ovarian Steroids Stimulate Adenosine Triphosphate-Sensitive Potassium (KATP) Channel Subunit Gene Expression and Confer Responsiveness of the Gonadotropin-Releasing Hormone Pulse Generator to KATP Channel Modulation

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