G Proteins and Autocrine Signaling Differentially Regulate Gonadotropin Subunit Expression in Pituitary Gonadotrope

Gonadotropin-releasing hormone (GnRH) acts at gonadotropes to direct the synthesis of the gonadotropins, follicle-stimulating hormone (FSH), and luteinizing hormone (LH). The frequency of GnRH pulses determines the pattern of gonadotropin synthesis. Several hypotheses for how the gonadotrope decodes GnRH frequency to regulate gonadotropin subunit genes differentially have been proposed. However, key regulators and underlying mechanisms remain uncertain. We investigated the role of individual G proteins by perturbations using siRNA or bacterial toxins. In LβT2 gonadotrope cells, FSHβ gene induction depended predominantly on Gαq/11, whereas LHβ expression depended on Gαs. Specifically reducing Gαs signaling also disinhibited FSHβ expression, suggesting the presence of a Gαs-dependent signal that suppressed FSH biosynthesis. The presence of secreted factors influencing FSHβ expression levels was tested by studying the effects of conditioned media from Gαs knockdown and cholera toxin-treated cells on FSHβ expression. These studies and related Transwell culture experiments implicate Gαs-dependent secreted factors in regulating both FSHβ and LHβ gene expression. siRNA studies identify inhibinα as a Gαs-dependent GnRH-induced autocrine regulatory factor that contributes to feedback suppression of FSHβ expression. These results uncover differential regulation of the gonadotropin genes by Gαq/11 and by Gαs and implicate autocrine and gonadotrope-gonadotrope paracrine regulatory loops in the differential induction of gonadotropin genes. The mechanism for differential control of gonadotropin gene induction by GnRH is not established. GnRH activates Gαs and Gαq/11, which modulate LH and FSH synthesis, respectively, by a mechanism including secreted factors. Different G proteins and autocrine signaling regulate the pattern of FSH and LH expression by GnRH. A novel G protein and autocrine signaling mechanism has been identified.