Desensitization of LH secretion by the gonadotrope is a hallmark of GnRH action unless it is administered or secreted in a pulsatile fashion. The cellular and molecular mechanisms of gonadotrope desensitization is poorly understood. A class of proteins discovered originally in yeast have been described as being involved in mammalian cell desensitization. Called regulators of G-protein signalling (RGS), one of these proteins (RGS-3) has been shown by us to inhibit GnRH-stimulated cellular inositol trisphosphate (IP3) levels, its mRNA is present in the gonadotropic aT3-1 cell line, and RGS is detected by antibodies in membranes of aT3-1 and pituitary cells. RGS3 is shown to bind the Gqa protein in vitro supporting the notion that RGSs act by binding G proteins, thus inhibiting G-protein coupling of the receptor to phospholipase C activation. Fifteen mammalian genes encoding RGSs have been identified.
The Specific Aims are to: (1) complete the preliminary characterization of RGS3 as participating in GnRH-induced desensitization; (2) Determine if other members of the 15 member RGS family are involved in GnRH-induced desensitization by screening RNA from GnRH-treated aT3-1 cells; (3) Investigate the role of RGS in GnRH-induced desensitization of LH secretion in purified rat pituitary gonadotropes. The experiments have the potential to provide a cellular and molecular explanation of GnRH-induced desensitization, and perhaps provide an entree to the wider issue of regulation of general gonadotrope responsiveness.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD034862-01A1
Application #
2026196
Study Section
Reproductive Endocrinology Study Section (REN)
Project Start
1997-04-10
Project End
2000-03-31
Budget Start
1997-04-10
Budget End
1998-03-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Physiology
Type
Schools of Dentistry
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294