NPY (neuropeptide Y)

2009-05-01   Massimiliano Ruscica , Elena Dozio , Paolo Magni 

Identity

HGNC
LOCATION
7p15.3
LOCUSID
ALIAS
PYY4
FUSION GENES

DNA/RNA

Note

History: NPY, first discovered in 1982 from pig brain, has been characterized as one of the most highly conserved neuroendocrine peptides throughout evolution. Its name derives from the single-letter code (Y) for the amino acid (aa) tyrosine, since it contains five tyrosine residues including an amidated C-terminal tyrosine residue. Moreover, there is 92% aa sequence identity for NPY between the cartilaginous fish, Torpedo marmorata, and mammals, which are separated by an evolutionary distance of more than 400 million years. These evidences indicate that NPY presumably has a critical physiological function and that interindividual variation at this locus is likely to be minimal. The NPY gene is about 8 kilobases (kb) in length with four small exons (each,

Description

NPY encompasses 7,669 bp of DNA on chromosome 7 (7p15.1) between 24290334 and 24298002 from pter.

Transcription

The NPY RNA transcript contains 4 exons and it is 551 bp, in lenght. In details, Exon 1 (86 bp) contains the 5-UTR, Exon 2 (188 bp) encodes the signal peptide and the main part of the mature NPY sequence, except the last base of arginine codon 35 and the last tyrosine codon. Exon 3 (82 bp) contains the last base of the arginine codon, the last tyrosine codon from the mature peptide, the glycine amide donor site, the dibasic cleavage site, and the main portion of C-terminal flanking peptide of NPY (CPON). Finally, Exon 4 (21 + 174 bp) includes the end of CPON and the 3-UTR.

Proteins

Description

The coding sequence (291 bp) of NPY gene synthetizes the pre-pro NPY (see diagram), a precursor peptide of 97 aa residues (size 10.8 kDa), which is cleaved after 28-aa, resulting in the pro-NPY, a 69-aa peptide. Pro-NPY undergoes cleavage by the proconverting enzymes (PC)1/3 and/or PC2 at a single dibasic site (Lys38-Arg39), releasing a 30-aa carboxyl terminal peptide, the C-flanking peptide of NPY (CPON), with so far unknown function and NPY1-39, which is further processed by a carboxypeptidase-like enzyme. The resulting NPY1-37 is finally amidated at its C-terminal end by the peptidylglycine-amidating monooxygenase (PAM) in a process that removes an additional aa (glycine) and produces the mature and biologically active peptide NPY1-36. Moreover, NPY can be further process, by two enzymes, dipeptidyl peptidase IV (DPPIV) and aminopeptidase P, into NPY3-36 and NPY2-36, respectively. NPY exhibits a three-dimensional structure called PP-fold, which is characterized by a harpin-like structure and by a type II beta-turn, connecting a polyproline-like type II helix (residues 14 to 30), thus leading to a close proximity of N- and C-terminal ends of the peptide.
Atlas Image
A schematic drawing of 97 aa pre-pro NPY which is further process up to the release of the mature and biologically active peptide NPY1-36 and the 30-aa CPON peptide.

Expression

The 36-aa NPY is one of the most abundant peptides expressed in numerous brain regions (i.e, hypothalamus, amygdala, hippocampus and cerebral cortex), as well as in the periphery (i.e, liver, heart, spleen, endothelial cells of blood vessels), showing both pre- and post-synaptic actions. However, the adrenal medulla is the primary source of circulating NPY.
In details, in the brain, it is synthesized by neurons of the arcuate (ARC) nucleus and it is active on the paraventricular (PVN), on the dorsomedial (DMN) nucleus, and on the A1 and C1 areas of the median preoptic area. In particular, in human, high levels of NPY mRNA were found in the dentate gyrus, caudate nucleus and putamen. In cerebral cortex the amount of NPY-immunoreactivity (NPY-ir) is present at the highest concentration in the cingulated and temporal cortices and at the lowest in the occipital lobe. NPY-labeled cells are also found in subcortical white matter, whereas this expression is negative in white matter areas away from the cortex. The striatum shows heterogeneous levels of NPY mRNA with a higher expression in the nucleus accumbens and the ventral region of the caudate. In general, NPY neurons also coexpress various neurotransmitters. In fact, ARC NPY subpopulation coexpresses the neuropeptide agouti-related peptide (AgRP) and the amino acid gamma-aminobutyric acid (GABA), whereas the brain stem subpopulation coexpresses the adrenergic transmitters, epinephrine and norepinephrine.
In the periphery, NPY is expressed in the sympathetic nervous system, co-stored and co-released with norepinephrine, as well as in non-sympathetic neurons in several organs including gastrointestinal tract, salivary glands, thyroid gland, pancreas, urogenital system, Schwann cells and heart. NPY is also present in cholinergic and non-cholinergic neurons (both central and peripheral) with anti-depressant, anti-convulsant and anti-nociceptive actions. In the mammalian intestine, NPY is present in both myenteric and submucous neurones that provide an extensive intrinsic innervation to smooth muscle layers and mucosal targets, respectively. NPY has been detected in glial cells and in olfactory Schwann cells, thereby potentially affording trophic support. NPY-ir appears mainly found in the renal tubules, whereas it seems absent in the glomerules. Interestingly, in infant colon, 41% of submucous plexus (a combination of Henles, intermediate and Meissners plexi) cell bodies are NPY-positive and co-localised with nitric oxide synthase immunoreactivity.

Localisation

Stored in cytoplasmatic secretory granules within the cell body and peptidergic nerve terminals. It is secreted upon specific stimuli.

Function

NPY has been involved in the regulation of a wide range of physiological central effects like the control of appetite, body weight homeostasis, the modulation of reproductive processes, the regulation of growth hormone secretion. Moreover, it is involved in the anxyolytic effect and sedation, in the endogenous anticonvulsant activity, in the circadian rhythm regulation, in learning and memory, in analgesia and hyperalgesia.
1) Food Intake
Being NPY a very potent stimulant of food ingestion, and mainly of carbohydrates, among these NPY-mediated actions, the major one is its role in the control of appetite, body weight homeostasis, and obesity. All these functions are mediated in humans by different receptor subtypes, so-called Y receptors: Y1-R, Y2-R, Y4-R, Y5-R and y6-R (a pseudogene in primates, with no shown activity as yet), which all belong to the large family of Gi-protein coupled receptors.
2) Cardiovascular function
NPY has also been described to mediate peripheral effects including the regulation of the cardiovascular system, vasoconstriction, the release of catecholamines by the adrenal medulla and vascular motility. About 25% of patients with acute heart failure were found to display an increase in circulating NPY levels. NPY has been proposed to be an useful marker for estimating the condition of patients suffering from cardiac diseases. In fact, plasma NPY immunoreactivity appeared elevated in patients with acute myocardial ischemia and in those with congestive heart failure. Moreover, NPY appears to enhance diuresis and natriuresis through direct tubular effects independent of its hemodynamic properties.
The vasopressive properties of NPY as well as its capacity to potentiate adrenergic responsiveness suggests that this peptide might be beneficial in the management of endotoxic shock. Indeed, in humans experiencing sepsis and septic shock, plasma levels of NPY are significantly increased and NPY-mediated vasoconstriction was shown to be preserved during endotoxemia.
3) Cancer
Besides these physiological events, in the context of the biology of cancer progression, recent evidence has extended the oncological relevance of NPY to endocrine-related cancers (see below).

Homology

The alignment of mature tetrapod NPY sequences reveals constant positions (91% identity) and only 4 positions are allowed to vary. In particular, amphibians sequences display an Arg-Lys replacement at position 19, porcine and bovine a Lys-Met replacement at position 17, ovine an Asp-Glu replacement at position 10, and chicken an Asn-Ser replacement at position 7. On the contrary, identical sequences of human mature NPY have been found in monkey, rat, rabbit, guinea pig, and alligator.

Mutations

Note

So far, in the literature there are many evidence which connect NPY and NPY receptors to a condition or disease, like hyperlipidemia, enhanced rate of atherosclerosis, increased body mass index (BMI), higher birth weigh, as well as alcohol dependence, depression and schizophrenia. To date there are reported only two non-synonymous sequence variants in the signal sequence part of NPY gene (p.L7P; 7th aa of the preproNPY, leucine, is changed to proline; rs16139) and c.64C>A (p.L22M; 22nd aa of the preproNPY, leucine, is changed to methionine; rs5571). The single nucleotide polymorphism (SNP) L7P was originally discovered in 1998 in Finnish and Dutch populations. It varies from 6% to 15% in the Caucasian populations and it seems to be totally absent or extremely low in oriental populations. L7P substitution is located in the signal peptide part of preproNPY and it is due to a single base substitution c.20T>C.

Implicated in

Entity name
Endocrine-related cancers
Note
Endocrine-related cancers are malignancies depending at least in part upon the trophic effect of specific hormones, and include breast, ovarian and prostate cancers, and to endocrine (pituitary tumors, adrenocortical lesions) and neuroendocrine (pheochromocytoma, neuroblastoma, gastroenteropancreatic tumors-PETs) tumors.
Oncogenesis
The involvement of NPY and NPY receptors (NPY-Rs) in the progression of endocrine-related cancers may be associated with: (a) expression of NPY-Rs in the context of the tumor, thus becoming a target of extratumorally secreted NPY proximal to the tumor. In this context, the presence of NPY-Rs may be targeted by specific drugs with either agonist or antagonist activity or by radiolabeled compounds (the universal ligand 125I-labeled PYY, the selective Y1-R 125I-labeled [Leu31, Pro34]-PYY and the selective Y2-R 125I-labeled PYY3-36); (b) in situ production of NPY. Tumor-produced NPY may act locally in a paracrine fashion and/or reach the bloodstream and generate systemic effects. The measurement of NPY plasma levels may have the value of a diagnostic marker; (c) a combination of expression of NPY-Rs and local production of NPY by the tumor. NPY effects may result in either promotion or suppression of cancer growth through paracrine mechanisms.
NPY is then involved in specific steps of cancer progression, like cell proliferation, matrix invasion, metastatization, and angiogenesis. Proliferative or anti-proliferative effects of NPY have been shown in different cell systems and appear mediated mainly through the Y1-R, which has been involved in the control of the proliferation of vascular smooth muscle and endothelial cells and injured glial cells. NPY has also been found to modulate the proliferation of hepatic stellate cells and neural crest-derived tumors.
NPY significantly enhances also angiogenesis in various ex vivo and in vivo models of angiogenesis, such as aortic sprouting, Matrigel plug assay, and ischemic hind limb revascularization. NPY-driven angiogenesis has been proposed to be bimodal at least in vitro (at low and high concentration, 10-12 and 10-8 M, respectively) and through oligomerization of Y1-, Y2-, and Y5-R. These data might explain the in vivo NPY-induced angiogenesis both in tissues that contain low NPY concentrations, such as the nonsympathetically innervated aorta or growing organs lacking a mature NPY system and in tissues containing high NPY concentrations, such as the heart, mature vessels or muscles during high sympathetic activity induced by stress, ischemia, or injury. Nevertheless, by using an in vitro assay to test the multistage process of metastasis (cell attachment to extracellular matrix (ECM), enzymatic degradation of ECM, and migration to fibronectin) it has been demonstrated that NPY affects tumor matrix invasion. In particular, it inhibits the invasion of murine Colon 26-L5 adenocarcinoma cells through a reconstituted basement membrane, whereas on both the DU145 and PC-3 human androgen independent prostate cancer cells it was not. In none of the tumor cell lines considered, as neither on LNCaP human androgen dependent prostate cancer cells NPY enhanced the haptotactic migration.
Entity name
Atherosclerosis
Note
In 1998 it has been reported that the P7 allele (p.P7) in the NPY signalling peptide could be a strongest genetic factor influencing serum cholesterol and low density lipo-protein (LDL) levels in obese subject. Two independent studies showed that: a) men with P7 substitution had a four-year increase in the mean and maximal common carotid intima-media thickness (IMT), b) increased carotid IMT in type 2 diabetes patients, c) obese subject with BMI> 30 Kg/m2 had increased serum total cholesterol and LDL cholesterol. On the contrary, in 443 children with a family history of cardiovascular disease (CVD) the Leu7Pro polymorphism was not associated with serum lipid values after adjustment for body weight in boys or girls, but may be associated with dietary response to LDL-cholesterol concentration in overweight boys with a family history of early-onset CVD.
Entity name
Obesity
Note
Although the role of NPY in the regulation of human feeding is not fully clear and there are several negative studies, in 2005 a study conducted on Dutch population of non-obese subjects, highlighted that both men and women, carried the L7P substitution, had higher mean BMI values. On the other hand, one conflicting study associated the p.L7P with lower BMI in premenopausal women.
Entity name
Diabetes
Note
The L7P polymorphism has been associated with onset of type 2 diabetes, impaired glucose tolerance and with a worse glycaemic balance in type 1 diabetic patients as measured by HbA1c levels. In addition, the preproNPY Pro7 carrier status, in middle-aged subjects, was a significant risk factor for type II diabetes and they were more insulin resistant and showed lower ghrelin levels compared to non-carriers. In general, healthy subjects with p.P7 allele have higher glucose, lower insulin and lower insulin/glucose ratio during rest, after meals, and during exercise.

Bibliography

Pubmed IDLast YearTitleAuthors
75298631995Changes in plasma concentrations of vasoactive neuropeptides in patients with sepsis and septic shock.Arnalich F et al
112074292000Characterization of NPY mRNA-expressing cells in the human brain: co-localization with Y2 but not Y1 mRNA in the cerebral cortex, hippocampus, amygdala, and striatum.Caberlotto L et al
124381442002Catecholamine and neuropeptide Y secretion from human adrenal chromaffin cells: effect of nicotine and KCl.Cavadas C et al
109490872000Neuropeptide Y family of peptides: structure, anatomical expression, function, and molecular evolution.Cerdá-Reverter JM et al
24172051985Anatomy and physiology of the neuroendocrine arcuate nucleus.Chronwall BM et al
90678401997Laminar distribution of neuropeptide Y-immunoreactive neurons in human prefrontal cortex during development.Delalle I et al
13122431992Neuropeptide Y and neuropeptide Y receptor subtypes in brain and peripheral tissues.Dumont Y et al
153373662004Introduction to the reviews on neuropeptide Y.Gehlert DR et al
79894941994Angiotensin-II mediates norepinephrine and neuropeptide-Y secretion in a human pheochromocytoma.Grouzmann E et al
108419822000The leucine (7)-to-proline (7) polymorphism in the signal peptide of neuropeptide Y is not associated with Alzheimer's disease or the link apolipoprotein E.Helisalmi S et al
117017042001Enhanced exercise-induced GH secretion in subjects with Pro7 substitution in the prepro-NPY.Kallio J et al
116892162001Leucine7 to proline7 polymorphism in the preproneuropeptide Y is associated with the progression of carotid atherosclerosis, blood pressure and serum lipids in Finnish men.Karvonen MK et al
35163121986Effects of monosodium L-glutamate administration on neuropeptide Y-containing neurons in the rat hypothalamus.Kerkérian L et al
157533672005Differential effects of neuropeptide Y on the growth and vascularization of neural crest-derived tumors.Kitlinska J et al
87388761996Evolution of neuropeptide Y, peptide YY and pancreatic polypeptide.Larhammar D et al
125760902003Impaired angiogenesis in neuropeptide Y (NPY)-Y2 receptor knockout mice.Lee EW et al
94015851997Time-dependent effects of ischaemia on neuropeptide Y mechanisms in pig renal vascular control in vivo.Malmström RE et al
121873942002Association analysis of genes involved in the leptin-signaling pathway with obesity in Brazil.Mattevi VS et al
65896111984Cloning, characterization, and DNA sequence of a human cDNA encoding neuropeptide tyrosine.Minth CD et al
112408282001Effect of prostatic neuropeptides on migration of prostate cancer cell lines.Nagakawa O et al
75232221994Neural sites of the human colon colocalize nitric oxide synthase-related NADPH diaphorase activity and neuropeptide Y.Nichols K et al
159261142005Leu7Pro polymorphism in the neuropeptide Y (NPY) gene is associated with impaired glucose tolerance and type 2 diabetes in Swedish men.Nordman S et al
126784992003Neuropeptide Y: the universal soldier.Pedrazzini T et al
147472362004Leucine 7 to proline 7 polymorphism in the preproneuropeptide Y is associated with proteinuria, coronary heart disease, and glycemic control in type 1 diabetic patients.Pettersson-Fernholm K et al
172043522007Role of neuropeptide Y and its receptors in the progression of endocrine-related cancer.Ruscica M et al
182795622008Leucine 7 to proline 7 polymorphism in the neuropeptide Y gene and changes in serum lipids during a family-based counselling intervention among school-aged children with a family history of CVD.Salminen M et al
38408101985Colocalization of neuropeptide Y immunoreactivity in brainstem catecholaminergic neurons that project to the paraventricular nucleus of the hypothalamus.Sawchenko PE et al
21742221990Signal epitopes in the three-dimensional structure of neuropeptide Y. Interaction with Y1, Y2, and pancreatic polypeptide receptors.Schwartz TW et al
92435151997Clonidine administration increases neuropeptide Y immunoreactivity and neuropeptide Y mRNA in the rat cerebral cortex neurons.Smiałowska M et al
24758841989Innervation of the thyroid. A study of the rat using retrograde tracing and immunocytochemistry.Sundler F et al
68960831982Neuropeptide Y--a novel brain peptide with structural similarities to peptide YY and pancreatic polypeptide.Tatemoto K et al
145856002003'Neuro'-peptides in glia: focus on NPY and galanin.Ubink R et al
172684192007Leu7Pro polymorphism of PreproNPY associated with an increased risk for type II diabetes in middle-aged subjects.Ukkola O et al
22802351990Elevation of plasma neuropeptide Y-like immunoreactivity and noradrenaline during myocardial ischaemia in man.Ullman B et al
33514301988Plasma levels of neuropeptide tyrosine Y (NPY) are increased in human sepsis but are unchanged during canine endotoxin shock despite raised catecholamine concentrations.Watson JD et al
84728451993Efficient amidation of C-peptide deleted NPY precursors by non-endocrine cells is affected by the presence of Lys-Arg at the C-terminus.Wulff BS et al
103428791999Daily changes in hypothalamic gene expression of neuropeptide Y, galanin, proopiomelanocortin, and adipocyte leptin gene expression and secretion: effects of food restriction.Xu B et al
96867581998Neuropeptide Y: a novel angiogenic factor from the sympathetic nerves and endothelium.Zukowska-Grojec Z et al
165681372006Polymorphisms in the NPY and AGRP genes and body fatness in Dutch adults.van Rossum CT et al
127408142003Semisynthesis and characterization of the first analogues of pro-neuropeptide y.von Eggelkraut-Gottanka R et al

Other Information

Locus ID:

NCBI: 4852
MIM: 162640
HGNC: 7955
Ensembl: ENSG00000122585

Variants:

dbSNP: 4852
ClinVar: 4852
TCGA: ENSG00000122585
COSMIC: NPY

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000122585ENST00000242152P01303
ENSG00000122585ENST00000242152A4D158
ENSG00000122585ENST00000405982P01303
ENSG00000122585ENST00000405982A4D158
ENSG00000122585ENST00000407573P01303
ENSG00000122585ENST00000407573A4D158

Expression (GTEx)

0
50
100
150

Pathways

PathwaySourceExternal ID
Adipocytokine signaling pathwayKEGGko04920
Adipocytokine signaling pathwayKEGGhsa04920
AlcoholismKEGGhsa05034
AlcoholismKEGGko05034
cAMP signaling pathwayKEGGhsa04024
cAMP signaling pathwayKEGGko04024
Regulation of lipolysis in adipocytesKEGGhsa04923
Signal TransductionREACTOMER-HSA-162582
Signaling by GPCRREACTOMER-HSA-372790
GPCR ligand bindingREACTOMER-HSA-500792
Class A/1 (Rhodopsin-like receptors)REACTOMER-HSA-373076
Peptide ligand-binding receptorsREACTOMER-HSA-375276
GPCR downstream signalingREACTOMER-HSA-388396
G alpha (i) signalling eventsREACTOMER-HSA-418594

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA128406954Weight gainDiseaseMultilinkAnnotationassociated24279860
PA258NPY1RGenePathwayassociated
PA31741NPY2RGenePathwayassociated

References

Pubmed IDYearTitleCitations
183856732008Genetic variation in human NPY expression affects stress response and emotion.138
198745742009Genetical genomic determinants of alcohol consumption in rats and humans.93
203517142011Poor replication of candidate genes for major depressive disorder using genome-wide association data.92
229799962012Neuropeptide Y, peptide YY and pancreatic polypeptide in the gut-brain axis.87
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
192400612009Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappaB signalling.75
195873572009A systematic meta-analysis of genetic association studies for diabetic retinopathy.57
210416082011Family-based analysis of genetic variation underlying psychosis-inducing effects of cannabis: sibling analysis and proband follow-up.48
203089902011Genome-wide copy number variation analysis in attention-deficit/hyperactivity disorder: association with neuropeptide Y gene dosage in an extended pedigree.47
205546942010Circadian clock gene polymorphisms in alcohol use disorders and alcohol consumption.45

Citation

Massimiliano Ruscica ; Elena Dozio ; Paolo Magni

NPY (neuropeptide Y)

Atlas Genet Cytogenet Oncol Haematol. 2009-05-01

Online version: http://atlasgeneticsoncology.org/gene/44438/npy