A regulator of G protein signaling, RGS3, inhibits gonadotropin-releasing hormone (GnRH)-stimulated luteinizing hormone (LH) secretion.
BACKGROUND
Luteinizing hormone secreted by the anterior pituitary gland regulates gonadal function. Luteinizing hormone secretion is regulated both by alterations in gonadotrope responsiveness to hypothalamic gonadotropin releasing hormone and by alterations in gonadotropin releasing hormone secretion. The mechanisms that determine gonadotrope responsiveness are unknown but may involve regulators of G protein signaling (RGSs). These proteins act by antagonizing or abbreviating interaction of Galpha proteins with effectors such as phospholipase Cbeta. Previously, we reported that gonadotropin releasing hormone-stimulated second messenger inositol trisphosphate production was inhibited when RGS3 and gonadotropin releasing hormone receptor cDNAs were co-transfected into the COS cell line. Here, we present evidence for RGS3 inhibition of gonadotropin releasing hormone-induced luteinizing hormone secretion from cultured rat pituitary cells.


RESULTS
A truncated version of RGS3 (RGS3T = RGS3 314-519) inhibited gonadotropin releasing hormone-stimulated inositol trisphosphate production more potently than did RSG3 in gonadotropin releasing hormone receptor-bearing COS cells. An RSG3/glutathione-S-transferase fusion protein bound more 35S-Gqalpha than any other member of the G protein family tested. Adenoviral-mediated RGS3 gene transfer in pituitary gonadotropes inhibited gonadotropin releasing hormone-stimulated luteinizing hormone secretion in a dose-related fashion. Adeno-RGS3 also inhibited gonadotropin releasing hormone stimulated 3H-inositol phosphate accumulation, consistent with a molecular site of action at the Gqalpha protein.


CONCLUSIONS
RGS3 inhibits gonadotropin releasing hormone-stimulated second messenger production (inositol trisphosphate) as well as luteinizing hormone secretion from rat pituitary gonadotropes apparently by binding and suppressing the transduction properties of Gqalpha protein function. A version of RGS3 that is amino-terminally truncated is even more potent than intact RGS3 at inhibiting gonadotropin releasing hormone-stimulated inositol trisphosphate production.
Neill
J D
JD
Department of Physiology and Biophysics, University of Alabama School of Medicine, Birmingham, AL 35294, USA. neill@uab.edu
Duck
L W
LW
Sellers
J C
JC
Musgrove
L C
LC
Kehrl
J H
JH
D000818:Animals; D019556:COS Cells; D020013:Calcium Signaling; D002478:Cells, Cultured; D005260:Female; D019204:GTP-Binding Proteins; D020690:GTPase-Activating Proteins; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007986:Luteinizing Hormone / Q000378:metabolism*; D010903:Pituitary Gland, Anterior / Q000378:metabolism*; D020710:RGS Proteins / Q000235:genetics / Q000502:physiology*; D051381:Rats; D011966:Receptors, LHRH / Q000378:metabolism; D012097:Repressor Proteins; D017384:Sequence Deletion
D020690:GTPase-Activating Proteins; D020710:RGS Proteins; D011966:Receptors, LHRH; D012097:Repressor Proteins; C415085:Rgs3 protein, mouse; C437714:Rgs3 protein, rat; D007987:Gonadotropin-Releasing Hormone; D015544:Inositol 1,4,5-Trisphosphate; D007986:Luteinizing Hormone; D019204:GTP-Binding Proteins; D020962:Heterotrimeric GTP-Binding Proteins