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

Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208

Address all correspondence and requests for reprints to: Jon E. Levine, 2205 Tech Drive, Hogan 2-160, Evanston, Illinois 60208. E-mail: jlevine{at}northwestern.edu.

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, 17β-estradiol (E₂), progesterone (P), or E₂+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 E₂+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, E₂+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 E₂+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) E₂+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.