The nervous system regulates the reproductive axis through the activity of the """"""""GnRH pulse generator,"""""""" neurons in the hypothalamus whose activity governs pulsatile release of gonadotropin-releasing hormone (GnRH). The amplitude and frequency of GnRH pulses are, in turn, regulated by physiological signals, some of which evoke sustained shifts in the activity of the GnRH pulse generator and hence, in overall reproductive state. Metabolic cues, for example, are clearly important for maintenance of GnRH pulsatility in adult animals, and in the deceleration of GnRH pulsatility that occurs under conditions of negative energy balance. Cellular and molecular mechanisms mediating physiological shifts in GnRH pulse generator activity remain unknown. These studies will test the hypothesis that metabolically-linked adjustments of GnRH pulse generator activity are mediated by regulation of ion channels, specifically those known to link cell metabolism to cell excitability - the ATP-sensitive potassium channels (K+ATP channels). The K+ATP channel closes upon binding AlP, leading to reduced cellular K+ permeability, membrane depolarization and thus, increased cell excitability; reduced intracellular ATP produces the opposite conditions, reducing cell excitability. Preliminary work implicates hypothalamic K+ATP channels activity in the modulatation of GnRH release. The proposed studies are therefore designed to determine whether K+ATP channel opening and closing in vivo lead to alterations in GnRH pulse generator activity (Aim 1), assess whether opening of K+ATP channels mediates inhibition of GnRH pulsatility during food-restriction (Aim 2), determine the molecular and functional properties of KATP channels in identified GnRH neurons [Aims 3,4], and determine whether suppression of hypothalamic K+ATP channel expression reverses effects of negative energy balance on GnRH pulsatility (Aim5) A transgenic mouse will also be developed (Aim 6) in which expressesion of overactive (open) K+ATP channel subunits will be targeted to GnRH neurons, permitting examination of the reproductive consequences of K+ATP channel hyperactivity in GnRH neurons. These studies may provide new and important information on cellular mechanisms mediating many major physiological alterations in GnRH pulse generator activity. They may also permit an understanding of how GnRH pulse generation is inhibited in feeding disorders such as anorexia nervosa, or in other hypogonadotropic states, such as functional hypothalamic amenorrhea associated with subclinical eating disorders or rigorous exercise training.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD020677-15
Application #
6719686
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
De Paolo, Louis V
Project Start
1996-03-01
Project End
2007-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
15
Fiscal Year
2004
Total Cost
$233,888
Indirect Cost
Name
Northwestern University at Chicago
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
160079455
City
Evanston
State
IL
Country
United States
Zip Code
60201
Zhao, Zhen; Park, Cheryl; McDevitt, Melissa A et al. (2009) p21-Activated kinase mediates rapid estradiol-negative feedback actions in the reproductive axis. Proc Natl Acad Sci U S A 106:7221-6
Acosta-Martínez, Maricedes; Luo, Ji; Elias, Carol et al. (2009) Male-biased effects of gonadotropin-releasing hormone neuron-specific deletion of the phosphoinositide 3-kinase regulatory subunit p85alpha on the reproductive axis. Endocrinology 150:4203-12
Demissie, Marek; Lazic, Milos; Foecking, Eileen M et al. (2008) Transient prenatal androgen exposure produces metabolic syndrome in adult female rats. Am J Physiol Endocrinol Metab 295:E262-8
Huang, Wenyu; Acosta-Martinez, Maricedes; Horton, Teresa H et al. (2008) Fasting-induced suppression of LH secretion does not require activation of ATP-sensitive potassium channels. Am J Physiol Endocrinol Metab 295:E1439-46
Xu, Xiaoyang; Zhao, Zhen; Qin, Lidong et al. (2008) Fluorescence recovery assay for the detection of protein-DNA binding. Anal Chem 80:5616-21
McDevitt, Melissa A; Glidewell-Kenney, Christine; Jimenez, Mariana A et al. (2008) New insights into the classical and non-classical actions of estrogen: Evidence from estrogen receptor knock-out and knock-in mice. Mol Cell Endocrinol 290:24-30
Foecking, Eileen M; McDevitt, Melissa A; Acosta-Martinez, Maricedes et al. (2008) Neuroendocrine consequences of androgen excess in female rodents. Horm Behav 53:673-92
Huang, Wenyu; Acosta-Martinez, Maricedes; Levine, Jon E (2008) 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. Endocrinology 149:2423-32
Acosta-Martinez, Maricedes; Levine, Jon E (2007) Regulation of KATP channel subunit gene expression by hyperglycemia in the mediobasal hypothalamus of female rats. Am J Physiol Endocrinol Metab 292:E1801-7
McDevitt, Melissa A; Glidewell-Kenney, Christine; Weiss, Jeffrey et al. (2007) Estrogen response element-independent estrogen receptor (ER)-alpha signaling does not rescue sexual behavior but restores normal testosterone secretion in male ERalpha knockout mice. Endocrinology 148:5288-94

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