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Query: UNIPROT:P06889 (Mol)
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In mammalian species, ovulation occurs following a massive release of hypothalamic gonadotropin-releasing hormone (GnRH). Several chemicals, including norepinephrine (NE) and neuropeptide Y (NPY), are responsible for the initiation and/or magnitude and duration of this pre-ovulatory GnRH surge. In the central nervous system, NE neural cell bodies are located in the brainstem; some are co-localized with NPY neurons and/or co-express the NE transporter (NET) gene which dictates NET protein production. The activity of NET at NE terminals is critical for synaptic NE function. In the rabbit, coitus induces a hypothalamic NE release which precedes the GnRH surge. We hypothesize that the coital stimulus is transmitted to the brainstem and transformed and integrated into GnRH-stimulating signals via NE, NET and/or NPY. However, very little is known about the distribution of cells expressing NET, NPY and tyrosine hydroxylase (TH, the rate-limiting enzyme of NE synthesis) in this species. Therefore, we utilized the sensitive in situ hybridization technique to identify the presence of these messages in conjunction with the location of NE cells, the latter being marked by dopamine beta-hydroxylase (DBH), the specific enzyme for NE synthesis. Three non-mated New Zealand White does were perfused with 4% paraformaldehyde and their brainstems were sectioned at 20-micron thick between 2 mm caudal to the obex and the rostral pons. Serial sections were immunohistochemically stained for DBH and hybridized with rabbit-specific TH and NET cRNAs and a human NPY probe. The data suggest that several DBH-positive areas in the medulla expressed one or more messages, i.e. the lateral tegmentum (A1) and the nucleus of the solitary tract (A2) expressed all three mRNAs, the area postrema (AP) contained NET and TH mRNAs but not NPY cells. In the pons, the locus coeruleus (LC), subnucleus of coeruleus (LCs) and lateral tegmental nuclei (A5) expressed NET and TH mRNAs but contained little or no NPY message. The distribution patterns of TH and NET appeared to be similar in the LC, LCs, A2 and AP.
Brain Res Mol Brain Res 1997 Sep
PMID:Topographic comparison of the expression of norepinephrine transporter, tyrosine hydroxylase and neuropeptide Y mRNA in association with dopamine beta-hydroxylase neurons in the rabbit brainstem. 933 34

Recently, the cDNA encoding the Y4 neuropeptide Y (NPY) receptor cDNA was cloned from a rat genomic library. The Y4 receptor is characterized by having a high affinity for pancreatic polypeptide (PP) and peptide YY (PYY). By using in situ hybridization histochemistry with 35S-labelled riboprobes, we have visualized the cellular expression of mRNA encoding the Y4 receptor protein in the rat dorsal vagal complex at the light microscopical level. High densities of silver grains were observed over neurones of the dorsal vagal motor nucleus, and over neurones of a subregion of the nucleus of the solitary tract known as the subnucleus gelatinosus. Furthermore, cells within the ventral margin of the area postrema expressed high levels of Y4 mRNA. These observations indicate that circulating PP and/or NPY/PYY via the blood-brain barrier-free area postrema and subpostremal area could influence neurones of the dorsal vagal complex with profound influence on numerous homeostatic mechanisms governed by this nuclear complex.
Brain Res Mol Brain Res 1997 Aug
PMID:The neuropeptide Y (Y4) receptor is highly expressed in neurones of the rat dorsal vagal complex. 937 29

We have isolated Xenopus laevis cDNA and genomic clones encoding the neuropeptide Y (NPY) mRNA and gene using a probe from the human NPY gene. The longest open reading frame in the cDNA encodes a peptide 76% identical to human prepro-NPY and 73% identical to rat prepro-NPY. The putative mature Xenopus NPY (XNPY) peptide is 94% identical to both human and rat peptides. A genomic clone containing 422 base pairs of 5'-flanking sequences and the 5'-end of the mRNA was also isolated. Primer extension analysis was used to map the transcription initiation site of the Xenopus NPY gene. Comparison of the 5'-flanking sequences of the Xenopus laevis, human, and rat NPY genes resulted in areas of high conservation, including the TATA box and the CT box previously shown to interact with Sp1-like proteins. Distribution of the Xenopus NPY message was analyzed by Northern analysis and RNAse protection. XNPY transcripts were not detected in whole developing embryo RNA, but were detected in adult frog brain RNA. We have also conducted preliminary studies of the XNPY promoter, utilizing an XNPY/chloramphenicol acetyl-transferase fusion construct. This study has demonstrated that Xenopus NPY shares a high degree of identity to its human and rat counterparts and that this homology extends to the gene, which contains similar cis-elements positioned near the transcription start site.
Mol Cell Endocrinol 1994 May
PMID:Isolation and characterization of the Xenopus laevis cDNA and genomic homologs of neuropeptide Y. 939 31

Acetylcholine stimulation of bovine chromaffin cells results in increased norepinephrine and epinephrine secretion accompanied by a corresponding increase in synthesis. The addition of neuropeptide Y (NPY) to the culture medium prevents the increase in catecholamine synthesis but not secretion. Treatment of chromaffin cells with nicotine produces a concentration-dependent increase in tyrosine hydroxylase activity (IC50 = 1.2 microM) that is reduced if NPY is present during stimulation. Tyrosine hydroxylase activity decreases in a concentration-dependent fashion if increasing amounts of NPY are included in the culture medium, IC50 = 0.2 nM. Treatment with pertussis toxin completely prevents the effect of NPY. The rank order of potency for inhibition of tyrosine hydroxylase activity is NPY > or = [Leu31,Pro34]NPY > or = peptide YY > NPY2-36 > NPY13-36 > NPY18-36 > or = NPY26-36 >> NPY1-30, suggesting a NPY-Y1 receptor subtype. Examination of the effect of NPY on nicotine stimulation of chromaffin cell protein phosphorylation showed that NPY produces a concentration-dependent decrease in a 60-kDa protein, IC50 = 6.4 nM. The effect of NPY is pertussis toxin-sensitive. The rank order of potency is [Leu31,Pro34]NPY > or = NPY >> NPY18-36. Immunoprecipitation confirmed the identity of the 60-kDa protein as tyrosine hydroxylase.
Mol Pharmacol 1997 Dec
PMID:Neuropeptide Y inhibits chromaffin cell nicotinic receptor-stimulated tyrosine hydroxylase activity through a receptor-linked G protein-mediated process. 941 12

Rats treated with kainic acid develop limbic seizures and have elevated levels of circulating catecholamines resulting from an extensive stimulation of the adrenal gland. We investigated the levels of several constituents of chromaffin granules in rat adrenal medulla after injection of kainic acid. This treatment increased mRNA steady-state levels of enkephalin, neuropeptide Y and chromogranin B 2-6-fold. Elevated levels of these constituents were found as early as 2 h after treatment and lasted up to 24 h. Chromogranin A and secretogranin II mRNA levels, on the other hand, remained unchanged. Adrenal catecholamine concentrations were reduced by 80%. Pre-treatment of rats with thiopental prior to kainic acid prevented seizures, the decline in catecholamines and the elevation of enkephalin and neuropeptide Y mRNAs but not that of chromogranin B. On the other hand, the peripherally acting ganglionic blocker chlorisondamine did not protect from the kainic acid-induced up-regulation of chromogranin B mRNA, suggesting that chromogranin B mRNA may be regulated by a direct effect of kainic acid on chromaffin cells. The pattern of changes in mRNA expression differed from that seen after insulin hypoglycemia or reserpine treatment. Thus, stimulation of the splanchnic innervation in vivo by various means leads to an individual and independent regulation of granule constituents by quite different mechanisms.
Brain Res Mol Brain Res 1997 Nov
PMID:Limbic seizures induce neuropeptide and chromogranin mRNA expression in rat adrenal medulla. 942 5

1. Regulation of pulsatile secretion of growth hormone (GH) relies on hypothalamic neuronal loops, major transmitters involved in their operation are growth hormone releasing hormone (GHRH) synthetized mostly in arcuate nucleus (ARC) neurons, and somatostatin (SRIH), synthetized both in hypothalamus periventricular (PVe) and ARC neurons. 2. Neurons synthetizing both peptides can inhibit each other in a reciprocal manner. Other neuropeptides synthetized in ARC neurons, such as galanin, or in ARC interneurons, such as neuropeptide Y (NPY), are able to modulate synthesis and release of GHRH and SRIH into the hypothalamohypophyseal portal system. 3. In addition, the hitherto uncharacterized endogenous ligand of the recently cloned growth hormone releasing peptide receptor, expressed mostly in the ARC, triggers GH release, presumably by actions on ARC interneurons. 4. Thyroid, gonadal, and adrenal steroid hormones also affect the GHRH-SRIH balance; a differential distribution of sex steroid receptors in the ARC and the PVe is likely to account for the different pattern of GH secretion in male and female animals. 5. Growth hormone itself is able to inhibit the amplitude of GH secretory episodes and to increase their frequency, by entering the brain (presumably by receptor-mediated internalization at the level of the choroid plexus) and acting subsequently on ARC neurons. 6. At the pituitary level, major neurotransmitters regulating GH cells act on receptors of the VIP/PACAP/GHRH family and of the somatostatin family, in particular, sst2 and sst3. Those are coupled to accumulation of cAMP as a second messenger. 7. In addition, patch-clamp experiments and measurement of intracellular Ca2+ indicate that GH cells present characteristic, GHRH-dependent, but self-maintained Ca2+ spikes and [Ca2+]i transients, which reflect adaptive mechanisms to constraints of episodic release. 8. Recent data on transcription factors affecting GH gene expression and somatotrope differentiation are also summarized. 9. Regulation and differentiation of somatotropes also depend upon paracrine processes within the pituitary itself and involve growth factors and several neuropeptides, for instance, vasoactive intestinal peptide, angiotensin 2, endothelin, and activin. 10. Finally, characteristic changes occur in the GH secretory pattern under discrete, pathological conditions, such as abnormal growth and dwarfism, diabetes, and acromegaly, as well as during inflammatory processes.
Cell Mol Neurobiol 1998 Feb
PMID:Hypothalamic and hypophyseal regulation of growth hormone secretion. 952 32

Somatostatin expression in trisomy 16 mouse neuronal cultures has been studied to investigate the effects of the presence of an extra copy of the pre-pro-somatostatin (ppSS) gene on mouse chromosome 16. The immunoreactivity for somatostatin (SS) was considered in mixed cultures of neurons and glia cells and in neuron-enriched cultures as well as that for neuropeptide Y, glutamic acid decarboxylase, and gamma-enolase immunoreactivity the genes of which are not present on mouse chromosome 16. ppSS and pre-pro-neuropeptide Y (ppNPY) mRNA expression was evaluated and SS immunoreactivity in neurons analyzed by a morphometrical study. The extra copy of the ppSS gene resulted in a significantly increased level of the transcript in trisomic cultures, whereas the expression of the other neuropeptides did not differ. The absence of glial cells in these cultures reduced the number of SS-positive neurons making their number comparable in the trisomic and control cultures. Thus, in spite of higher expression of the ppSS mRNA in trisomic cultures, the determination of this peptidergic phenotype was influenced by the presence of neuroglial cells.
J Mol Neurosci 1998 Apr
PMID:Somatostatin expression in TS16 mouse brain cultures. 969 51

The ligand binding site of neuropeptide Y (NPY) at the rat Y1 (rY1,) receptor was investigated by construction of mutant receptors and [3H]NPY binding studies. Expression levels of mutant receptors that did not bind [3H]NPY were examined by an immunological method. The single mutations Asp85Asn, Asp85Ala, Asp85Glu and Asp103Ala completely abolished [3H]NPY binding without impairing the membrane expression. The single mutation Asp286Ala completely abolished [3H]NPY binding. Similarly, the double mutation Leu34Arg/Asp199Ala totally abrogated the binding of [3H]NPY, whereas the single mutations Leu34Arg and Asp199Ala decreased the binding of [3H]NPY 2.7- and 5.2-fold, respectively. The mutants Leu34Glu, Pro35His as well as Asp193Ala only slightly affected [3H]NPY binding. A receptor with a deletion of the segment Asn2-Glu20 or with simultaneous mutations of the three putative N-terminal glycosylation sites, displayed no detectable [3H]NPY binding, due to abolished expression of the receptor at the cell surface. Taken together, these results suggest that amino acids in the N-terminal part as well as in the first and second extracellular loops are important for binding of NPY, and that Asp85 in transmembrane helix 2 is pivotal to a proper functioning of the receptor. Moreover, these studies suggest that the putative glycosylation sites in the N-terminal part are crucial for correct expression of the rY1 receptor at the cell surface.
Mol Cell Endocrinol 1998 Apr 30
PMID:The ligand binding site of NPY at the rat Y1 receptor investigated by site-directed mutagenesis and molecular modeling. 970 87

The discovery of leptin has generated an extraordinary interest in the field of obesity but also in the understanding of the relationship between metabolic status and the neuroendocrine system. Following the initial demonstration that leptin administration to fasting mice can 'protect' neuroendocrine secretions and prevent the changes that are associated with fasting, the concept has emerged that a normal leptin secretion is a prerequisite for normal neuroendocrine secretions. Several unfavorable metabolic situations are associated with low plasma leptin, increased secretion of hypothalmic neuropeptide Y (NPY), and hypogonadism, and a causal relationship has been evoked. Severe dietary restriction in juvenile female rats is associated with low plasma leptin and sexual immaturity. Cessation of food restriction leads to immediate increase in plasma leptin followed 4 days later by vaginal opening. If food restriction is maintained, central leptin infusion can induce sexual maturation, thus demonstrating that leptin can act as a signal for the onset of puberty. In untreated type-I diabetic rats, hypogonadism is associated with very low plasma leptin and increased hypothalmic NYP synthesis and oestrous cyclicity. Fasting rapidly inhibits growth hormone (GH) secretion in association with low plasma leptin and elevated hypothalmic NPY. Central infusion of leptin to fasting rats was able to completely prevent the collapse of GH secretion and to maintain a normal low NPY synthesis. In summary, normally elevated plasma levels appear to be a prerequisite for normal GH and gonadotropin secretion in the rat. Degradation of metabolic conditions results in a rapid reduction of circulating leptin that could represent the signal for several alterations of neuroendocrine secretions. At the level of the hypothalamus, leptin could act on NPY neurons to transduce part or all of this 'metabolic' message. The possibility that changing plasma levels for leptin also affect peripheral endocrine targets, such as pituitary, ovary, adrenal or pancreas, is likely since these endocrine organs express functional long-term leptin receptors.
Mol Cell Endocrinol 1998 May 25
PMID:Metabolic control of sexual function and growth: role of neuropeptide Y and leptin. 972 77

To investigate the possible link between neuropeptide Y (NPY) and depression, we analyzed NPY and its receptors in different limbic-related regions in the Flinder sensitive line (FSL), a genetic animal model of depression. In situ hybridization histochemistry was used to measure mRNA expression levels of NPY and NPY receptors, Y1 and Y2, in the FSL as compared to the control Flinder resistant Line rats (FRL). In the FSL rats, NPY mRNA expression levels were significantly decreased in the nucleus accumbens and CA regions, but increased in the arcuate nucleus and anterior cingulate cortex. Y1 receptor mRNA expression was decreased in different cortical regions (retrosplenial, anterior cingulate, and occipital) and in the hippocampal dentate gyrus. Y2 mRNA expression levels did not differ between FSL and FRL animals. The effect of the antidepressant drug fluoxetine (a serotonin reuptake inhibitor) in the two rat strains was also studied. There was an increase of the NPY mRNA hybridization signal in the arcuate nucleus of both strains following the antidepressant treatment (10 micromol/kg; daily for 14 days). However, in other brain regions, fluoxetine administration caused a differential effect on the induction of NPY-related genes in the two rat strains: in the CA region and dentate gyrus NPY mRNA expression was increased in the FSL, but decreased in the FRL. In contrast, Y1 mRNA levels tended to be decreased by fluoxetine in the nucleus accumbens of the FSL rats, but increased in the FRL. These findings suggest an involvement of the Y1, but not the Y2, receptor subtype in depressive disorder. Overall, the results appear to sustain the importance of the FSL rats as an animal model of depression in view of the impairment of NPY genes and the ability of fluoxetine treatment to normalize NPY-related gene expression selectively in this strain.
Brain Res Mol Brain Res 1998 Aug 15
PMID:Alterations in neuropeptide Y and Y1 receptor mRNA expression in brains from an animal model of depression: region specific adaptation after fluoxetine treatment. 972 78


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