Ghrelin inhibits prolactin secretion in prepubertal rats.

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Abstract

Ghrelin, a novel 28-amino-acid peptide primarily expressed in stomach and hypothalamus, has recently emerged as the endogenous ligand for the GH-secretagogue receptor with ability to stimulate GH secretion in humans and rats. In addition, ghrelin also stimulates prolactin (PRL) secretion in humans. However, its role in the regulation of PRL secretion in rats remains largely unknown. In this context, the present experiments were carried out to analyze the effects of ghrelin on PRL secretion in male and female rats. In detail, the ontogeny and potential sexual dimorphism in the PRL response to ghrelin was evaluated. In addition, the hypothalamic and/or pituitary site of primary action of ghrelin, as well as the possible interactions between ghrelin and other neurotransmitters, as nitric oxide, dopamine, serotonin or excitatory amino acids, in the precise control of PRL secretion were assessed. Experiments were conducted in prepubertal male and female animals. Systemic (i.p.) and central (i.c.v.) administration of ghrelin significantly inhibited PRL secretion. Such an inhibitory effect became evident after day 10 of age, was similar in males and females, and was also observed in hyperprolactinemic aged female rats. In contrast, however, challenge of pituitary samples in vitro with increasing doses of ghrelin (10(-9)-10(-7)M) failed to inhibit PRL secretion. Analysis of interactions between ghrelin and other systems involved in the control of PRL secretion revealed that neither blockade of dopaminergic receptors with domperidone, nor enhancement of serotoninergic tone with fluoxetine + 5-hydroxytryptophan altered the inhibitory response to ghrelin in terms of PRL secretion. Similarly, blockade of nitric oxide synthases with L-nitro-arginine-methyl ester failed to modify the magnitude of ghrelin-induced inhibition of PRL secretion, whereas ghrelin was unable to further decrease serum PRL levels after activation of ionotropic excitatory amino acid receptors by administration of NMDA or AMPA. In conclusion, our data indicate that ghrelin is able to inhibit PRL secretion in male and female rats, likely through an extrapituitary primary site of action that is independent of nitric oxide, dopamine, and serotonin systems.

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Localization of nitric oxide synthase indicating a neural role for nitric oxide.

D Bredt, P M Hwang, S H Snyder (1990)

Nitric oxide (NO), apparently identical to endothelium-derived relaxing factor in blood vessels, is also formed by cytotoxic macrophages, in adrenal gland and in brain tissue, where it mediates the stimulation by glutamate of cyclic GMP formation in the cerebellum. Stimulation of intestinal or anococcygeal nerves liberates NO, and the resultant muscle relaxation is blocked by arginine derivatives that inhibit NO synthesis. It is, however, unclear whether in brain or intestine, NO released following nerve stimulation is formed in neurons, glia, fibroblasts, muscle or blood cells, all of which occur in proximity to neurons and so could account for effects of nerve stimulation on cGMP and muscle tone. We have now localized NO synthase protein immunohistochemically in the rat using antisera to the purified enzyme. We demonstrate NO synthase in the brain to be exclusively associated with discrete neuronal populations. NO synthase is also concentrated in the neural innervation of the posterior pituitary, in autonomic nerve fibres in the retina, in cell bodies and nerve fibres in the myenteric plexus of the intestine, in adrenal medulla, and in vascular endothelial cells. These prominent neural localizations provide the first conclusive evidence for a strong association of NO with neurons.

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A prolactin-releasing peptide in the brain.

M Sekiguchi, T Asano, Y Masuo … (1998)

Hypothalamic peptide hormones regulate the secretion of most of the anterior pituitary hormones, that is, growth hormone, follicle-stimulating hormone, luteinizing hormone, thyroid-stimulating hormone and adrenocorticotropin. These peptides do not regulate the secretion of prolactin, at least in a specific manner, however. The peptides act through specific receptors, which are referred to as seven-transmembrane-domain receptors or G-protein-coupled receptors. Although prolactin is important in pregnancy and lactation in mammals, and is involved in the development of the mammary glands and the promotion of milk synthesis, a specific prolactin-releasing hormone has remained unknown. Here we identify a potent candidate for such a hormone. We first proposed that there may still be unknown peptide hormone factors that control pituitary function through seven-transmembrane-domain receptors. We isolated the complementary DNA encoding an 'orphan' receptor (that is, one for which the ligand is unknown). This receptor, hGR3, is specifically expressed in the human pituitary. We then searched for the hGR3 ligand in the hypothalamus and identified a new peptide, which shares no sequence similarity with known peptides and proteins, as an endogenous ligand. We show that this ligand is a potent prolactin-releasing factor for rat anterior pituitary cells; we have therefore named this peptide prolactin-releasing peptide.

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Structural divergence of human ghrelin. Identification of multiple ghrelin-derived molecules produced by post-translational processing.

Hiroshi Hosoda, Masayasu Kojima, Kenji Kangawa … (2003)

Ghrelin, a novel 28-amino acid peptide with an n-octanoyl modification at Ser(3), was isolated from rat stomach and found to be an endogenous ligand for the growth-hormone secretagogue receptor (GHS-R). This octanoyl modification is essential for ghrelin-induced GH release. We report here the purification and identification of human ghrelin from the stomach, as well as structural analysis of the human ghrelin gene and quantitation of changes in plasma ghrelin concentration before and after gastrectomy. Human ghrelin was purified from the stomach by gel filtration and high performance liquid chromatography, using a ghrelin-specific radioimmunoassay and an intracellular calcium influx assay on a stable cell line expressing GHS-R to test the fractions. In the course of purification, we isolated human ghrelin of the expected size, as well as several other ghrelin-derived molecules. Classified into four groups by the type of acylation observed at Ser(3); these peptides were found to be non-acylated, octanoylated (C8:0), decanoylated (C10:0), and possibly decenoylated (C10:1). All peptides found were either 27 or 28 amino acids in length, the former lacking the C-terminal Arg(28), and are derived from the same ghrelin precursor through two alternative pathways. The major active form of human ghrelin is a 28-amino acid peptide octanoylated at Ser(3), as was found for rat ghrelin. Synthetic octanoylated and decanoylated ghrelins produce intracellular calcium increases in GHS-R-expressing cells and stimulate GH release in rats to a similar degree. Both ghrelin and the ghrelin-derived molecules were found to be present in plasma as well as stomach tissue. Plasma levels of immunoreactive ghrelin after total gastrectomy in three patients were reduced to approximately half of their pre-gastrectomy values, after which they gradually increased. This suggests that the stomach is the major source of circulating ghrelin and that other tissues compensate for the loss of ghrelin production after gastrectomy.