Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01178 (oxytocin)
 15,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The gas nitric oxide (NO) is an important messenger in brain signaling. Along with many other functions, NO is thought to influence the expression and/or release of various hypothalamic hormones (corticotropin-releasing hormone (CRH), gonadotropin-releasing hormone (GnRH) and vasopressin). To learn more about the role of NO in neuroendocrine mechanisms, we studied in mutant mice lacking neuronal isoform of NO synthase (nNOS) the cellular expression of CRH, neurophysin (the carrier protein of vasopressin/oxytocin) and pro-opiomelanocortin (POMC), as well as of the POMC-derived peptides beta-endorphin (beta-END), alpha-melanocyte-stimulating hormone (alpha-MSH) and corticotropin (ACTH) by use of immunohistochemistry and in situ hybridization. Additionally, the remaining NO-generating capacities of the nNOS minus mice were investigated by NADPH-diaphorase histochemistry and citrulline immunohistochemistry as well as by immunohistochemical localization and Western blot analysis of endothelial NOS (eNOS) and nNOS isoforms. Amongst all hypothalamic peptides under investigation, only beta-END was found to be altered in mutant mice. A morphometric analysis of beta-END producing neurons of the arcuate nucleus revealed that significantly less cells were immunoreactive in mutant mice, whereas the expression of the precursor POMC as well as of other POMC-derived peptides was found to be unchanged. In addition to that, fewer beta-END-immunoreactive fibers were found in the paraventricular nucleus of nNOS minus mice in comparison to wild-type animals. Hence, the reduction of hypothalamic beta-END is probably a posttranslational event that might reflect a disturbed endorphinergic innervation of those hypothalamic neurons which normally express nNOS.
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PMID:Expression of hypothalamic peptides in mice lacking neuronal nitric oxide synthase: reduced beta-END immunoreactivity in the arcuate nucleus. 987 4

Previous studies on the mediobasal hypothalamus (MBH) of rats, rhesus monkeys and goats have detected episodic increases in multiunit activity (MUA volleys) which immediately precede a pulse of luteinizing hormone (LH). These volleys are considered to reflect the activity of the gonadotropin-releasing hormone (GnRH) pulse generator. Our understanding of this system would be greatly enhanced if it were possible to study the electrophysiological aspects of this system at the single cell level; such an approach requires anesthesia of the animals (as in the classic studies on the oxytocin and vasopressin systems). Although it is widely held that anesthetic agents disrupt the processes regulating LH release, little is known about their specific effects on the dynamics of this system. Using on-line electrophysiological techniques in addition to subsequent radioimmunoassay for LH, we have found that anesthesia by ketamine is compatible with the continued production of MUA volleys and LH pulses in gonadectomized rats. In contrast to the hypothermia induced by the LH pulse-suppressing anesthetic sodium pentobarbitone, a small rise in core temperature occurs following ketamine. The present findings offer the prospect of detailed electrophysiological analysis of GnRH pulse generator activity in rats maintained under general anesthesia.
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PMID:Ketamine-induced general anesthesia is compatible with gonadotropin-releasing hormone pulse generator activity in gonadectomized rats: prospects for detailed electrophysiological studies in vivo. 1054 3

Optic nerve formation in mouse involves interactions between netrin-1 at the optic disk and the netrin-1 receptor DCC (deleted in colorectal cancer) expressed on retinal ganglion cell (RGC) axons. Deficiency in either protein causes RGC pathfinding defects at the disk leading to optic nerve hypoplasia (). Here we show that further along the visual pathway, RGC axons in netrin-1- or DCC-deficient mice grow in unusually angular trajectories within the ventral hypothalamus. In heterozygous Sey(neu) mice that also have a small optic nerve, RGC axon trajectories appear normal, indicating that the altered RGC axon trajectories in netrin-1 and DCC mutants are not secondarily caused by optic nerve hypoplasia. Intrinsic hypothalamic patterning is also affected in netrin-1 and DCC mutants, including a severe reduction in the posterior axon projections of gonadotropin-releasing hormone neurons. In addition to axon pathway defects, antidiuretic hormone and oxytocin neurons are found ectopically in the ventromedial hypothalamus, apparently no longer confined to the supraoptic nucleus in mutants. In summary, netrin-1 and DCC, presumably via direct interactions, govern both axon pathway formation and neuronal position during hypothalamic development, and loss of netrin-1 or DCC function affects both visual and neuroendocrine systems. Netrin protein localization also indicates that unlike in more caudal CNS, guidance about the hypothalamic ventral midline does not require midline expression of netrin.
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PMID:Altered midline axon pathways and ectopic neurons in the developing hypothalamus of netrin-1- and DCC-deficient mice. 1055 99

Many neuropeptides are involved in the control of sexual behaviour at the central level. Among these, the most studied are adrenocorticotropin, alpha-melanocyte stimulating hormone, oxytocin and opioid peptides. This attempt to review old and new neuropharmacological, biochemical and psychobiological studies in this field, shows that all these neuropeptides apparently facilitate sexual behaviour, except for opioid peptides, which inhibit sexual performance, in most of the species studied so far (rats, mice, monkeys and humans). However, gonadotropin-releasing hormone, corticotropin releasing factor, neuropeptide Y, galanin, cholecystokinin, substance P and vasoactive intestinal peptide may be also involved in the control of sexual behaviour. Apparently, corticotropin releasing factor, neuropeptide Y and cholecystokinin inhibit, while substance P and vasoactive intestinal peptide facilitate, sexual behaviour. In contrast, gonadotropin-releasing hormone has been reported to exert a facilitative, inhibitory or no effect at all on sexual behaviour. Galanin was also shown either to facilitate or inhibit sexual behaviour. The above-mentioned putative role of the neuropeptides in sexual behaviour derives mainly from studies done in rats. In these studies, neuropeptides, their antisera or drugs that act as agonists or antagonists of neuropeptide receptors, were tested for their effect on sexual behaviour after systemic, intracerebroventricular, or intracerebral administration. The latter were infused into brain areas relevant for sexual behaviour, such as the medial preoptic area, and the ventromedial and paraventricular nuclei of the hypothalamus. The above studies show that little information is available on the mechanisms by which neuropeptides influence sexual behaviour. Also unclear is whether the above neuropeptides influence the anticipatory phase (sexual arousal and/or motivation) or the consummatory phase (performance) of sexual behaviour, except for opioid peptides. New information about the role of neuropeptides may come from the application of molecular biology and genetic manipulation techniques to the study of sexual behaviour. Of these, FOS protein determination, antisense oligonucleotides aimed at the neutralisation of neuropeptide and/or neuropeptide receptor mRNAs in specific brain areas, and gene ablation seem the most promising. Although still in the early stages, it is likely that these methodologies will provide new insights into the role of neuropeptides in the control of sexual behaviour.
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PMID:Neuropeptides and sexual behaviour. 1064 21

The integrated regulation of luteinizing hormone (LH) from the anterior pituitary gland is vital to the functioning of the ovulatory cycle in the female and consists of several components acting at different time points. The best-studied is the rapid release of LH elicited by gonadotropin-releasing hormone (GnRH). The so-called primary (immediate early) response genes (PRGs), including c-fos, regulate relatively long-term activities, such as mitosis, protein synthesis, protein release and cell differentiation. Regular ovulatory cycles occur as a result of interaction of several peptide factors including the primary factor, GnRH and oxytocin, although GnRH and oxytocin do not have identical activities. We wished to determine whether oxytocin could mediate changes in expression of c-fos protein and compare its effects with those of GnRH. Anterior pituitary glands were collected from female rats at proestrus and a single-cell suspension prepared. Cells were incubated with oxytocin or GnRH at selected concentrations for various times. C-fos protein was extracted and submitted to Western blot analysis. Other cells were stained immunohistochemically for c-fos and LH following incubation with the peptides and fixation. There was an increase in c-fos protein from 15 to 60 min in Western blots of cells from all incubations. After immunohistochemistry, it was observed that both oxytocin (100 nM) and GnRH (100 nM) increased the percentage of cells that expressed c-fos protein (p < 0.001) and of cells that expressed LH (p < 0.001). The responses to the peptides were concentration dependent. We found that neither all LH-containing cells expressed c-fos, nor all c-fos-containing cells immunostained for LH. The effects of the peptides were not the same. High concentrations of GnRH (1 microM) induced the appearance of a higher percent of LH-containing cells having c-fos than did 10 nM GnRH (p < 0.01), whereas a lower percent of LH-containing cells with c-fos were observed when the oxytocin concentration was raised from 10 nM to 1 microM (p < 0.02). It appears, therefore, that the two peptides have different regulatory effects on LH-containing cells, indicating the possibility of specialized function. The results emphasize the suggestion that stimulation of LH secretion is not the sole index of gonadotrope-directed activity by a peptide. Collectively, these results indicate that the peptides oxytocin and GnRH are able to modulate processes that are associated with longer-term activities of gonadotropes and also demonstrate that specific subpopulations of LH-containing gonadotropes are stimulated to express c-fos.
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PMID:Regulation of C-fos protein in gonadotrope cells by oxytocin and gonadotropin-releasing hormone. 1085 91

The gas nitric oxide is a messenger in brain signaling. In the hypothalamo-hypophyseal system nitric oxide is involved in the control of the expression and/or release of peptide hormones (corticotropin-releasing hormone, gonadotropin-releasing hormone, vasopressin and oxytocin). Nitric oxide synthase (NOS), the enzyme generating nitric oxide, is abundantly present in the magnocellular nuclei of the rat hypothalamus. Its localization in the human hypothalamus is less well studied. Hence, we investigated the anatomical distribution of neuronal nitric oxide synthase in the human supraoptic nucleus by use of immunohistochemical and enzyme histochemical techniques. The immunohistochemical localization of NOS was studied in 31 matched human hypothalami (13 control cases, eight depressed patients and ten schizophrenics). NADPH-diaphorase studies were carried out on seven additional hypothalami (three normal brains, four schizophrenics). Apparent inter-individual differences exist with regard to the occurrence of the enzyme in supraoptic neurons. In a majority of cases no immunostaining or histochemical reaction for the enzyme was observed. In seven cases (three controls, two schizophrenics, two depressives) a population of nitrergic nerve cells was seen in the dorsomedial part of the nucleus. This group of cells also stained for NADPH-diaphorase. Also, there were a few NOS-immunopositive neurons scattered throughout the nucleus. Additionally, thin NADPH-diaphorase positive fibers were observed to cross the nucleus. Our data show that, unlike the rat, the human supraoptic nucleus contains only a small number of nitrergic neurons. No correlation was found between the expression of the enzyme in supraoptic neurons and the psychiatric status of the patients.
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PMID:Low and infrequent expression of nitric oxide synthase/NADPH-diaphorase in neurons of the human supraoptic nucleus: a histochemical study. 1111 9

Normal action of the female ovulatory cycle is dependent on a surge of luteinizing hormone (LH) from the pituitary. Regulation of the levels of LH is therefore vital to reproductive function. It has long been established that gonadotropin-releasing hormone (GnRH) is an important component of the regulatory processes. Other peptides, including oxytocin and neuropeptide Y (NPY), have also been observed to affect LH activities. However, the possibility of the concurrent actions of these peptides has rarely been considered despite their documented presence in the hypophyseal blood during pro-oestrus. In this study, the direct effects of oxytocin and NPY on LH release were studied, as well as the effects of both peptides simultaneously. Also, pituitaries were stimulated with GnRH, and the effects of pre-exposure of the pituitary tissue to oxytocin or NPY were investigated. Further, the effect of oxytocin and NPY together on GnRH stimulation of LH release was determined. Anterior pituitaries were collected from adult female rats on the morning of pro-oestrus. Hemipituitaries were cut in two and placed in a chamber of a perifusion system. The pituitary tissue was perifused with medium alone, oxytocin and NPY, separately or in combination, for 2 h after an initial 100-min equilibration period with no peptide present. Fractions of eluate were collected and LH was measured by radioimmunoassay. LH output was stimulated by both oxytocin (p < 0.01) and NPY (p < 0.02). Furthermore, the addition of NPY to oxytocin during the perifusion elicited a further increase in LH release (p < 0.05). The pituitary tissue was exposed to a 4-min pulse of GnRH after 220 min. Stimulation of LH release by GnRH was synergistically augmented by exposure of the tissue to either oxytocin (p < 0.01) or NPY (p < 0.05) for the immediately preceding 2 h. When NPY was added to oxytocin in the perifusion medium, stimulation of LH release by GnRH was increased even further (p < 0.05). Oxytocin also synergistically enhanced the effect of a second, primed GnRH pulse, whereas the effect of NPY was less robust. This study therefore demonstrated that LH release is modified in the presence of oxytocin, NPY or GnRH alone, and also that combinations of the peptides produce further variations in LH output. Therefore, the concentrations of LH that are present in vivo are likely to be at least partly the result of the co-ordinated effects of combinations of peptides acting on the pituitary.
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PMID:Release of luteinizing hormone from the anterior pituitary gland in vitro can be concurrently regulated by at least three peptides: gonadotropin-releasing hormone, oxytocin and neuropeptide Y. 1140 82

The study was designed to determine whether the ability of central oxytocin (OT) to stimulate gonadotropin-releasing hormone (GnRH) on the afternoon of proestrus (PE) in the cycling female rat is mediated at the level of GnRH terminals within the median eminence (ME), or at higher hypothalamic levels where GnRH cell bodies and axons are located. Determining the location of this OT effect in vivo has proven difficult. Therefore, an in vitro system utilizing ME or basal hypothalamic (BH) explants containing GnRH terminals, or GnRH neurons including the cell bodies, axons and terminals, respectively, were harvested from regular cycling female rats at 15:00 h on PE or diestrus (DI). The explants were allowed to preincubate in Krebs Ringer Bicarbonate Buffer containing glucose, ascorbic acid, calcium, and a metalloprotease inhibitor (KRBG) and enriched with 95% O(2)/5% CO(2) at 37 degrees C until a stable baseline release of GnRH was achieved (30 min). The 0.05 level of probability was used as the minimum criterion of significance in all experiments. The ability of OT (10(-15)--10(-9) M) to stimulate the release of GnRH was determined in both ME and BH explants on PE and DI. The results demonstrated a sensitive, dose-dependent ability of OT to stimulate GnRH release from PE BH explants which was observed only in PE. Furthermore, OT failed to significantly stimulate GnRH release from ME explants on either PE or DI. The data indicate that the PE BH explant paradigm can be used to examine the manner and mechanisms by which OT influences GnRH release on the afternoon of PE. Furthermore, the results indicate for the first time that the stimulatory action of OT by itself on preovulatory GnRH release in cycling female rats is not mediated at the level of the GnRH terminals within the ME, but requires neuronal interactions and mechanisms within the BH explants.
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PMID:Central stimulatory influence of oxytocin on preovulatory gonadotropin-releasing hormone requires more than the median eminence. 1147 20

Dwyer has suggested that peptide receptors evolved from self-aggregating peptides so that peptide receptors should incorporate regions of high homology with the peptide ligand. If one considers self-aggregation to be a particular manifestation of molecular complementarity in general, then it is possible to extend Dwyer's hypothesis to a broader set of peptides: complementary peptides that bind to each other. In the latter case, one would expect to find homologous copies of the complementary peptide in the receptor. Thirteen peptides, 10 of which are not known to self-aggregate (amylin, ACTH, LHRH, angiotensin II, atrial natriuretic peptide, somatostatin, oxytocin, neurotensin, vasopressin, and substance P), and three that are known to self-aggregate (insulin, glucagon, and gastrin), were chosen. In addition to being self-aggregating, insulin and glucagon are also known to bind to each other, making them a mutually complementary pair. All possible combinations of the 13 peptides and the extracellular regions of their receptors were investigated using bioinformatic tools (a total of 325 combinations). Multiple, statistically significant homologies were found for insulin in the insulin receptor; insulin in the glucagon receptor; glucagon in the glucagon receptor; glucagon in the insulin receptor; and gastrin in gastrin binding protein and its receptor. Most of these homologies are in regions or sequences known to contribute to receptor binding of the respective hormone. These results suggest that the Dwyer hypothesis for receptor evolution may be generalizable beyond self-aggregating to complementary peptides. The evolution of receptors may have been driven by small molecule complementarity augmented by modular evolutionary processes that left a "molecular paleontology" that is still evident in the genome today. This "paleontology" may allow identification of peptide receptor sites.
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PMID:Molecular complementarity III. peptide complementarity as a basis for peptide receptor evolution: a bioinformatic case study of insulin, glucagon and gastrin. 1229 71

In order to fulfill their roles in neuroendocrine regulation, specific hypothalamic neurons are devoted to produce and deliver biologically active peptides to the pituitary gland. The biosynthesis and release of peptides are strictly controlled by afferents to these hypothalamic neurons. Cell-specific expression and biosynthetic regulation largely relies on transcription from the gene promoter for which the 5(')-flanking regions of the peptidergic genes contain essential elements. Cell-specific transcription factors employ these regulatory elements to exert their control over the expression of the peptidergic gene. This article explores the properties of regulatory elements of the major hypothalamic peptides, somatostatin, growth hormone-releasing hormone, gonadotropin-releasing hormone, thyrotropin-releasing hormone, corticotropin-releasing hormone, vasopressin and oxytocin, and the transcription factors acting on them. These transcription factors are often endpoints of signal transduction pathways that can be activated by neurotransmitters or steroid hormones. Others are essential to provide cell-specific expression of the peptidergic gene during development and mature regulation.
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PMID:Regulation of gene promoters of hypothalamic peptides. 1238 30


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