Potential regulatory roles for G protein-coupled receptor kinases and beta-arrestins in gonadotropin-releasing hormone receptor signaling.
GnRH stimulates gonadotropin secretion, which desensitizes unless the releasing hormone is secreted or administered in a pulsatile fashion. The mechanism of desensitization is unknown, but as the GnRH receptor is G protein coupled, it might involve G protein-coupled receptor kinases (GRKs). Such kinases phosphorylate the intracellular regions of seven-transmembrane receptors, permitting beta-arrestin to bind, which prevents the receptor from activating G proteins. Here, we tested the effect of GRKs and beta-arrestins on GnRH-induced inositol trisphosphate (IP3) production in COS cells transfected with the GnRH receptor complementary DNA. GRK2, -3, and -6 overexpression inhibited IP3 production by 50-75% during the 30 sec of GnRH treatment. Coexpression of GRK2 and beta-arrestin-2 suppressed GnRH-induced IP3 production more than that of either alone. Immunocytochemical staining of rat anterior pituitary revealed that all cells expressed GRK2, -3, and -6; all cells also expressed the beta-arrestins. Western blots on cytosolic extracts of rat pituitaries revealed the presence of GRK2/3 and beta-arrestin-1 and -2. The expression of GRKs and beta-arrestins by gonadotropes and their inhibition of GnRH-stimulated IP3 production in COS-1 cells expressing the GnRH receptor suggest a potential regulatory role for the GRK/beta arrestin paradigm in GnRH receptor signaling.
Neill
J D
JD
Department of Physiology and Biophysics, University of Alabama, Birmingham 35294-0005, USA. neill@uab.edu
Duck
L W
LW
Musgrove
L C
LC
Sellers
J C
JC
D000818:Animals; D019390:Arrestins / Q000032:analysis / Q000378:metabolism*; D019556:COS Cells; D002417:Cattle; D019204:GTP-Binding Proteins / Q000378:metabolism*; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology; D007150:Immunohistochemistry; D007295:Inositol Phosphates / Q000096:biosynthesis; D007700:Kinetics; D010766:Phosphorylation; D010903:Pituitary Gland, Anterior / Q000737:chemistry; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis / Q000378:metabolism*; D011966:Receptors, LHRH / Q000502:physiology*; D015398:Signal Transduction; D014162:Transfection; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
C000605256:Arrb1 protein, rat; C000605257:Arrb2 protein, rat; D019390:Arrestins; D007295:Inositol Phosphates; D011966:Receptors, LHRH; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D007987:Gonadotropin-Releasing Hormone; D020794:Receptor Protein-Tyrosine Kinases; D019204:GTP-Binding Proteins