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NPY (neuropeptide Y)

Written2009-05Massimiliano Ruscica, Elena Dozio, Paolo Magni
Dipartimento di Endocrinologia, Fisiopatologia e Biologia Applicata, Università degli Studi di Milano, Italy (MR, PM); Dipartimento di Morfologia Umana e Scienze Biomediche Città Studi, Università degli Studi di Milano, Italy (ED)

(Note : for Links provided by Atlas : click)

Identity

Alias_symbol (synonym)PYY4
Other alias
HGNC (Hugo) NPY
LocusID (NCBI) 4852
Atlas_Id 44438
Location 7p15.3  [Link to chromosome band 7p15]
Location_base_pair Starts at 24323807 and ends at 24331484 bp from pter ( according to hg19-Feb_2009)  [Mapping NPY.png]
Fusion genes
(updated 2016)
MYBPC1 (12q23.2) / NPY (7p15.3)NCL (2q37.1) / NPY (7p15.3)

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, <200 base pairs [bp]) separated by three introns of approximately 965, 4300, and 2300 bp.
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.

Protein

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.
 
  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 Henle's, intermediate and Meissner's 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

Note
  
Entity 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 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 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 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.
  

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Citation

This paper should be referenced as such :
Ruscica, M ; Dozio, E ; Magni, P
NPY (neuropeptide Y)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(4):404-408.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/NPYID44438ch7p15.html


External links

Nomenclature
HGNC (Hugo)NPY   7955
Cards
AtlasNPYID44438ch7p15
Entrez_Gene (NCBI)NPY  4852  neuropeptide Y
AliasesPYY4
GeneCards (Weizmann)NPY
Ensembl hg19 (Hinxton)ENSG00000122585 [Gene_View]  chr7:24323807-24331484 [Contig_View]  NPY [Vega]
Ensembl hg38 (Hinxton)ENSG00000122585 [Gene_View]  chr7:24323807-24331484 [Contig_View]  NPY [Vega]
ICGC DataPortalENSG00000122585
TCGA cBioPortalNPY
AceView (NCBI)NPY
Genatlas (Paris)NPY
WikiGenes4852
SOURCE (Princeton)NPY
Genetics Home Reference (NIH)NPY
Genomic and cartography
GoldenPath hg19 (UCSC)NPY  -     chr7:24323807-24331484 +  7p15.3   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)NPY  -     7p15.3   [Description]    (hg38-Dec_2013)
EnsemblNPY - 7p15.3 [CytoView hg19]  NPY - 7p15.3 [CytoView hg38]
Mapping of homologs : NCBINPY [Mapview hg19]  NPY [Mapview hg38]
OMIM162640   
Gene and transcription
Genbank (Entrez)AI198311 AK312156 BC029497 DQ893335 DQ896651
RefSeq transcript (Entrez)NM_000905
RefSeq genomic (Entrez)NC_000007 NC_018918 NG_016148 NT_007819 NW_004929329
Consensus coding sequences : CCDS (NCBI)NPY
Cluster EST : UnigeneHs.1832 [ NCBI ]
CGAP (NCI)Hs.1832
Alternative Splicing GalleryENSG00000122585
Gene ExpressionNPY [ NCBI-GEO ]   NPY [ EBI - ARRAY_EXPRESS ]   NPY [ SEEK ]   NPY [ MEM ]
Gene Expression Viewer (FireBrowse)NPY [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)4852
GTEX Portal (Tissue expression)NPY
Protein : pattern, domain, 3D structure
UniProt/SwissProtP01303   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP01303  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP01303
Splice isoforms : SwissVarP01303
PhosPhoSitePlusP01303
Domaine pattern : Prosite (Expaxy)PANCREATIC_HORMONE_1 (PS00265)    PANCREATIC_HORMONE_2 (PS50276)   
Domains : Interpro (EBI)Pancreatic_hormone-like    Pancreatic_hormone-like_CS   
Domain families : Pfam (Sanger)Hormone_3 (PF00159)   
Domain families : Pfam (NCBI)pfam00159   
Domain families : Smart (EMBL)PAH (SM00309)  
Domain structure : Prodom (Prabi Lyon)Pancreatic_hormone-like (PD001267)   
Conserved Domain (NCBI)NPY
DMDM Disease mutations4852
Blocks (Seattle)NPY
PDB (SRS)1QFA    1RON   
PDB (PDBSum)1QFA    1RON   
PDB (IMB)1QFA    1RON   
PDB (RSDB)1QFA    1RON   
Structural Biology KnowledgeBase1QFA    1RON   
SCOP (Structural Classification of Proteins)1QFA    1RON   
CATH (Classification of proteins structures)1QFA    1RON   
SuperfamilyP01303
Human Protein AtlasENSG00000122585
Peptide AtlasP01303
HPRD01214
IPIIPI00001506   
Protein Interaction databases
DIP (DOE-UCLA)P01303
IntAct (EBI)P01303
FunCoupENSG00000122585
BioGRIDNPY
STRING (EMBL)NPY
ZODIACNPY
Ontologies - Pathways
QuickGOP01303
Ontology : AmiGOG-protein coupled receptor binding  response to yeast  G-protein coupled receptor activity  receptor binding  neuropeptide hormone activity  calcium channel regulator activity  extracellular region  extracellular space  extracellular space  cell  Golgi apparatus  calcium ion transport  movement of cell or subcellular component  G-protein coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger  neuropeptide signaling pathway  synaptic transmission  digestion  behavior  feeding behavior  blood circulation  regulation of blood pressure  cell proliferation  adult feeding behavior  antibacterial humoral response  antifungal humoral response  central nervous system neuron development  cerebral cortex development  neuron projection development  regulation of appetite  positive regulation of appetite  innate immune response  defense response to Gram-negative bacterium  defense response to Gram-positive bacterium  
Ontology : EGO-EBIG-protein coupled receptor binding  response to yeast  G-protein coupled receptor activity  receptor binding  neuropeptide hormone activity  calcium channel regulator activity  extracellular region  extracellular space  extracellular space  cell  Golgi apparatus  calcium ion transport  movement of cell or subcellular component  G-protein coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger  neuropeptide signaling pathway  synaptic transmission  digestion  behavior  feeding behavior  blood circulation  regulation of blood pressure  cell proliferation  adult feeding behavior  antibacterial humoral response  antifungal humoral response  central nervous system neuron development  cerebral cortex development  neuron projection development  regulation of appetite  positive regulation of appetite  innate immune response  defense response to Gram-negative bacterium  defense response to Gram-positive bacterium  
Pathways : KEGGAdipocytokine signaling pathway    Alcoholism   
REACTOMEP01303 [protein]
REACTOME Pathways375276 [pathway]   418594 [pathway]   
NDEx NetworkNPY
Atlas of Cancer Signalling NetworkNPY
Wikipedia pathwaysNPY
Orthology - Evolution
OrthoDB4852
GeneTree (enSembl)ENSG00000122585
Phylogenetic Trees/Animal Genes : TreeFamNPY
HOVERGENP01303
HOGENOMP01303
Homologs : HomoloGeneNPY
Homology/Alignments : Family Browser (UCSC)NPY
Gene fusions - Rearrangements
Fusion : MitelmanMYBPC1/NPY [12q23.2/7p15.3]  [t(7;12)(p15;q23)]  
Fusion: TCGAMYBPC1 12q23.2 NPY 7p15.3 PRAD
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerNPY [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)NPY
dbVarNPY
ClinVarNPY
1000_GenomesNPY 
Exome Variant ServerNPY
ExAC (Exome Aggregation Consortium)NPY (select the gene name)
Genetic variants : HAPMAP4852
Genomic Variants (DGV)NPY [DGVbeta]
DECIPHER (Syndromes)7:24323807-24331484  ENSG00000122585
CONAN: Copy Number AnalysisNPY 
Mutations
ICGC Data PortalNPY 
TCGA Data PortalNPY 
Broad Tumor PortalNPY
OASIS PortalNPY [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICNPY  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDNPY
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch NPY
DgiDB (Drug Gene Interaction Database)NPY
DoCM (Curated mutations)NPY (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)NPY (select a term)
intoGenNPY
NCG5 (London)NPY
Cancer3DNPY(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM162640   
Orphanet
MedgenNPY
Genetic Testing Registry NPY
NextProtP01303 [Medical]
TSGene4852
GENETestsNPY
Huge Navigator NPY [HugePedia]
snp3D : Map Gene to Disease4852
BioCentury BCIQNPY
ClinGenNPY
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD4852
Chemical/Pharm GKB GenePA255
Clinical trialNPY
Miscellaneous
canSAR (ICR)NPY (select the gene name)
Probes
Litterature
PubMed271 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineNPY
EVEXNPY
GoPubMedNPY
iHOPNPY
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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