# NPY

## Overview
The NPY gene encodes the neuropeptide Y protein, a 36-amino acid peptide that is a member of the neuropeptide family. Neuropeptide Y is a highly conserved protein that plays a crucial role in various physiological processes, including the regulation of energy balance, appetite, and stress response. It is categorized as a neuropeptide due to its function as a signaling molecule in the nervous system. The NPY gene is expressed predominantly in the central nervous system, particularly in the hypothalamus, where it influences feeding behavior and energy homeostasis by interacting with specific G-protein-coupled receptors (GPCRs) such as Y1, Y2, Y4, and Y5 (Loh2015Regulation; Walther2011Neuropeptide). Beyond its role in appetite regulation, neuropeptide Y is involved in modulating anxiety, circadian rhythms, and cardiovascular functions, highlighting its multifaceted impact on human health (Mercer2011The). The clinical significance of NPY is underscored by its association with various conditions, including mood disorders, cardiovascular diseases, and metabolic disturbances, making it a potential target for therapeutic interventions (Shah2009Neuropeptide; Wu2011Central).

## Structure
Neuropeptide Y (NPY) is a 36-amino acid peptide with a primary structure characterized by a high content of tyrosine and proline residues. Notably, it contains five tyrosine residues and lacks cysteine, phenylalanine, methionine, and valine (Tatemoto1982Neuropeptide). The secondary structure of NPY includes a type II proline helix at the N-terminus and an alpha-helix spanning residues 15-32, forming a hairpin-like fold known as the PP-fold (Gehlert2004Introduction; Cabrele2000Molecular). This structure is stabilized by hydrophobic interactions between the N-terminal polyproline-II-like helix and the C-terminal alpha-helix (Allen1987Molecular).

The tertiary structure of NPY is compact, with a globular conformation similar to that of the avian pancreatic polypeptide, featuring a left-handed polyproline-II-like helix and an alpha-helix (Allen1987Molecular). The C-terminus of NPY is amidated, a modification essential for its biological activity (Gehlert2004Introduction). NPY does not typically form quaternary structures, existing primarily as a monomer or dimer with antiparallel packing of helical units (Cabrele2000Molecular).

## Function
Neuropeptide Y (NPY) is a 36-amino acid peptide that plays a significant role in regulating energy homeostasis and appetite in humans. It is one of the most potent orexigenic agents, meaning it stimulates appetite, primarily through its action in the hypothalamus, particularly the arcuate nucleus (ARC) (Loh2015Regulation; Mercer2011The). NPY exerts its effects by binding to G-protein-coupled receptors, including Y1, Y2, Y4, Y5, and y6, with Y1 and Y2 being the most abundant (Loh2015Regulation).

In the central nervous system, NPY is involved in various physiological processes beyond appetite regulation, such as anxiety, circadian rhythm, and cardiovascular function (Mercer2011The). NPY neurons coexpress agouti-related protein (AgRP) and gamma-aminobutyric acid (GABA), which are involved in inhibiting proopiomelanocortin (POMC) neurons, thereby promoting food intake (Loh2015Regulation). NPY also influences energy expenditure by modulating thermogenesis in brown adipose tissue and affecting fat storage (Loh2015Regulation).

NPY functions as a neuroproliferative factor, promoting cell proliferation in the olfactory epithelium and potentially in central nervous system stem cells, indicating its role in neurogenesis (Hansel2001Neuropeptide). This multifaceted role of NPY underscores its importance in maintaining energy balance and its potential implications in obesity and metabolic disorders.

## Clinical Significance
Mutations and alterations in the expression of the NPY gene are associated with several diseases and conditions. In mood and anxiety disorders, lower levels of NPY are observed in patients with posttraumatic stress disorder (PTSD) and depression, suggesting a role in stress resilience and emotional regulation (Schmeltzer2016Neuropeptide; Wu2011Central). Genetic polymorphisms in NPY, such as those affecting the promoter region, are linked to increased amygdala activation and reduced stress resilience, contributing to anxiety and depressive symptoms, especially in individuals with early childhood adversity (Wu2011Central).

In cardiovascular diseases, NPY gene polymorphisms are significantly associated with early-onset coronary artery disease (CAD). Variants like the rs16147 SNP are linked to higher plasma NPY levels and increased CAD risk, particularly in young individuals (Shah2009Neuropeptide). The L7P polymorphism is associated with metabolic disturbances, including obesity and type 2 diabetes, due to its effects on NPY secretion and sympathetic activity (Pesonen2008NPY).

NPY also plays a role in alcohol-related disorders, with certain polymorphisms linked to increased alcohol consumption and dependence (Wu2011Central). These findings highlight the clinical significance of NPY gene mutations and expression alterations in various health conditions.

## Interactions
Neuropeptide Y (NPY) interacts with several G-protein-coupled receptors (GPCRs), including Y1, Y2, Y4, and Y5 receptors, which are involved in various physiological processes. NPY primarily binds to Y1R and Y5R, while Y2R binds both NPY and peptide YY (PYY) with similar affinities (Walther2011Neuropeptide). These receptors are distributed in the brain and peripheral tissues, where they signal via G proteins to inhibit adenylyl cyclases and cAMP synthesis (Walther2011Neuropeptide).

NPY receptor interactions include the formation of heterodimers, such as Y1R and Y5R, which internalize upon NPY treatment. This internalization is likely due to receptor internalization rather than disassociation, and Y1R stimulation can activate the heterodimer, possibly through transactivation of Y5R by Y1R (Czarnecka2019Neuropeptide). Y2R and Y5R do not form detectable heterodimers but co-localize and internalize together, indicating interaction within a larger protein complex (Czarnecka2019Neuropeptide).

The structural basis of NPY signaling through Y1R has been elucidated using cryo-electron microscopy, revealing that the C-terminal segment of NPY binds deep into the Y1R transmembrane core, contributing to high-affinity binding (Park2022Structural). These interactions highlight the complexity of NPY receptor interactions and suggest potential therapeutic targets for modulating receptor functionality.


## References


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[3. (Tatemoto1982Neuropeptide) K Tatemoto. Neuropeptide y: complete amino acid sequence of the brain peptide. Proceedings of the National Academy of Sciences, 79(18):5485–5489, September 1982. URL: http://dx.doi.org/10.1073/pnas.79.18.5485, doi:10.1073/pnas.79.18.5485. This article has 770 citations.](https://doi.org/10.1073/pnas.79.18.5485)

[4. (Cabrele2000Molecular) Chiara Cabrele and Annette G. Beck-Sickinger. Molecular characterization of the ligand-receptor interaction of the neuropeptide y family. Journal of Peptide Science, 6(3):97–122, March 2000. URL: http://dx.doi.org/10.1002/(SICI)1099-1387(200003)6:3<97::AID-PSC236>3.0.CO;2-E, doi:10.1002/(sici)1099-1387(200003)6:3<97::aid-psc236>3.0.co;2-e. This article has 274 citations and is from a peer-reviewed journal.](https://doi.org/10.1002/(SICI)1099-1387(200003)6:3)

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[8. (Park2022Structural) Chaehee Park, Jinuk Kim, Seung-Bum Ko, Yeol Kyo Choi, Hyeongseop Jeong, Hyeonuk Woo, Hyunook Kang, Injin Bang, Sang Ah Kim, Tae-Young Yoon, Chaok Seok, Wonpil Im, and Hee-Jung Choi. Structural basis of neuropeptide y signaling through y1 receptor. Nature Communications, February 2022. URL: http://dx.doi.org/10.1038/s41467-022-28510-6, doi:10.1038/s41467-022-28510-6. This article has 25 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/s41467-022-28510-6)

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