Cyclic Adenosine Monophosphate and Phorbol Ester, like Gonadotropin-Releasing Hormone, Stimulate the Biosynthesis of Luteinizing Hormone Polypeptide Chains in a Nonadditive Manner

Starzec, Anna; Jutisz, M; Counis, Raymond

doi:10.1210/mend-3-4-618

Cited by 52 publications

(26 citation statements)

References 35 publications

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“…Activators of PKC can stimulate protein synthesis in a variety of cell types, including pituitary gonadotropes (29). We therefore considered the hypothesis that the PMA-induced increase in relative plaque density was a consequence of enhanced protein synthesis.…”

Section: Resultsmentioning

confidence: 99%

Protein kinase C as a signal for exocytosis

Billiard

Koh

Babcock

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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We have studied signaling mechanisms that stimulate exocytosis and luteinizing hormone secretion in isolated male rat pituitary gonadotropes. As judged by reverse hemolytic plaque assays, phorbol-12-myristate-13-acetate (PMA) stimulates as many gonadotropes to secrete as does gonadotropin-releasing hormone (GnRH). However, PMA and GnRH use different signaling pathways. The secretagogue action of GnRH is not very sensitive to bisindolylmaleimide I, an inhibitor of protein kinase C, but is blocked by loading cells with a calcium chelator, 1,2-bis-(2-aminophenoxy)ethane-N,N,N,Ntetraacetic acid. The secretagogue action of PMA is blocked by bisindolylmaleimide I and is not very sensitive to the intracellular calcium chelator. GnRH induces intracellular calcium elevations, whereas PMA does not. As judged by amperometric measurements of quantal catecholamine secretion from dopamine-or serotonin-loaded gonadotropes, the secretagogue action of PMA develops more slowly (in several minutes) than that of GnRH. We conclude that exocytosis of secretory vesicles can be stimulated independently either by calcium elevations or by activation of protein kinase C.

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Section: Resultsmentioning

confidence: 99%

Protein kinase C as a signal for exocytosis

Billiard

Koh

Babcock

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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“…GnRH activates the PKC pathway as well as the PKA pathway; both of these increase ␣GSU expression (7,42,48). Reporter assays were therefore carried out to investigate the role of calcineurin in these signaling pathways for ␣GSU promoter activity.…”

Section: Downloaded Frommentioning

confidence: 99%

Calcineurin Mediates the Gonadotropin-Releasing Hormone Effect on Expression of Both Subunits of the Follicle-Stimulating Hormone through Distinct Mechanisms

Pnueli

Luo

Wang

et al. 2011

Molecular and Cellular Biology

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Gonadotropin-releasing hormone (GnRH) regulates the expression of all three gonadotropin genes, encoding the common ␣ subunit (␣GSU) and hormone-specific ␤ subunits, through the activation of several signal transduction pathways. We have shown that GnRH also upregulates calcineurin, and we hypothesized that calcineurin mediates the effects of GnRH on the transcription of the ␣GSU and follicle-stimulating hormone ␤ (FSH␤) genes through two of its targets: nuclear factor of activated T cells (NFAT) and CREB-regulated transcription coactivator (TORC). We show that calcineurin is essential for GnRH-induced expression of both genes but that NFAT and TORC1 play quite distinct roles in activating each gene. GnRH induces calcineurindependent nuclear import of NFAT3, which activates the ␣GSU promoter, while TORC1 also mediates GnRH activation of this promoter, but not through CREB. GnRH initially stimulates the degradation of TORC1 but protects the N terminus of the newly synthesized protein to enhance its activity. Calcineurin induces Nur77 expression, likely via NFAT3, and Nur77 interacts synergistically with TORC1 and CREB to increase FSH␤ promoter activity. Although TORC plays a role in the basal activity of the FSH␤ promoter, it does not interact with phosphorylated CREB and probably does not play a major role in direct GnRH signaling to this gene. TORC may be part of an alternatively regulated pathway, possibly involving cross talk with other stimulatory hormones.In the pituitary gonadotrope, the gonadotropin-releasing hormone (GnRH) plays a crucial role in activating the transcription of all three gonadotropin subunit genes: the common ␣ subunit (␣GSU) and the hormone-specific ␤ subunits encoding luteinizing hormone (LH␤) and follicle-stimulating hormone (FSH␤). Upon binding its G-protein-coupled receptor (GPCR), GnRH activates protein kinase C (PKC) and a number of well-characterized mitogen-activated protein kinase (MAPK) pathways, as well as elevating cyclic AMP (cAMP) levels to activate protein kinase A (PKA) (7,20,33,42,53). It also induces an increase in intracellular calcium levels by stimulating calcium release from intracellular stores as well as the influx of extracellular calcium through voltage-sensitive channels (7, 42). One of the effects of this increase in calcium levels is the activation of calmodulin and calmodulin-dependent kinases (CaMKs), which mediate various aspects of GnRH-induced signaling, including inhibition of histone deacetylases and regulation of extracellular signal-regulated kinase (ERK) activity (6,10,23,24,34,44,61). Calmodulin also activates the serine/threonine protein phosphatase calcineurin to regulate the expression of various genes (26). In the gonadotrope, calcineurin moderates the activity of the prolyl isomerase Pin1, facilitating its localization to the nucleus, where it plays an important role in GnRH signaling to several key transcription factors (36). Calcineurin also plays a role in the GnRH-induced derepression of FSH␤ gene expression in immature ␣T3-1 gonadotrope ...

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“…GnRH can also induce phospholipases D and A2, as well as a delayed production of cAMP however, the mechanisms involved remain obscure. Cyclic AMP has been shown to be capable of inducing increased expression of LH subunit genes and the release of newly synthesised LH [32,33] as well as an increased expression of the GnRH receptor [34] and NOS I [35,36] genes.…”

Section: Gnrh Receptor Signallingmentioning

confidence: 99%

Gonadotropin-releasing hormone and the control of gonadotrope function

et al. 2005

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-Normal gametogenesis and steroidogenesis is highly dependent on the pulsatile release of hypothalamic GnRH that binds high-affinity receptors present at the surface of pituitary gonadotrophs thereby triggering the synthesis and release of the gonadotropins LH and FSH. The mammalian GnRH receptor displays the classical heptahelical structure of G protein-coupled receptors with, however, a unique feature, the lack of a C-terminal tail. Accordingly, it does not desensitise sensu stricto, and internalises very poorly. It is now well established that GnRH stimulation induces the activation of a complex network of transduction pathways involved in the control of gonadotropin release and subunit gene expression. Other authors and ourselves have demonstrated that the GnRH action is associated with an increased complexity regarding gene regulation/cell function. Indeed GnRH affects the GnRH receptor gene itself and a number of additional genes that include some involved in cell signalling and auto-/paracrine regulation. The fact that GnRH regulates the expression of its own receptor, together with a host of other genes typically involved in its signal transduction cascades implies alteration/auto-adaptation in gonadotropic responsiveness. Furthermore, some of these genes respond differentially depending on whether the GnRH stimulation is intermittent or permanent suggesting specific roles in the dual process of activation/desensitisation. Thus, it can be assumed that the importance of pulsatility of GnRH action is closely related to, or dependent on, the inability of the GnRH receptor to desensitise. Moreover, multiple post-receptor events are crucial for both the regulation/plasticity of gonadotropic function and the maintenance of cell integrity.

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Cyclic Adenosine Monophosphate and Phorbol Ester, like Gonadotropin-Releasing Hormone, Stimulate the Biosynthesis of Luteinizing Hormone Polypeptide Chains in a Nonadditive Manner

Cited by 52 publications

References 35 publications

Protein kinase C as a signal for exocytosis

Protein kinase C as a signal for exocytosis

Calcineurin Mediates the Gonadotropin-Releasing Hormone Effect on Expression of Both Subunits of the Follicle-Stimulating Hormone through Distinct Mechanisms

Gonadotropin-releasing hormone and the control of gonadotrope function

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