Neuropeptide S receptor explained

The neuropeptide S receptor (NPSR) is a member of the G-protein coupled receptor superfamily of integral membrane proteins^[1] which binds neuropeptide S (NPS).^[2] It was formerly an orphan receptor, GPR154, until the discovery of neuropeptide S as the endogenous ligand. Increased expression of this gene in ciliated cells of the respiratory epithelium and in bronchial smooth muscle cells is associated with asthma. This gene is a member of the G protein-coupled receptor 1 family and encodes a plasma membrane protein. Mutations in this gene have also been associated with this disease.^[3]

Clinical significance

In the CNS, activation of the NPSR by NPS promotes arousal and anxiolytic-like effects.^{[4] [5]}

In addition, mututations in NPSR have been linked to a susceptibility to asthma (rs3249801, A107I).^[6] Hence NPSR has also been called GPRA (G protein-coupled receptor for asthma susceptibility). Activation of NPSR in the airway epithelium has a number of effects including upregulation of matrix metalloproteinases which are involved in the pathogenesis of asthma.^[7] It has been shown that activation of NPSR by NPS affects both gastrointestinal motility and mucosal permeability simultaneously. Aberrant signaling and upregulation of NPSR1 could potentially exacerbate dysmotility and hyperpermeability by local mechanisms in gastrointestinal functional and inflammatory reactions.^[8]

The very rare NPSR mutation Y206H, which makes the receptor more sensitive to NPS, may cause familial natural short sleep.^[9] This finding has not been investigated in animal models, and is sufficiently rare that a biobank study was unable to find other carriers to attempt a replication of the association with sleep duration.^[10]

Further reading

• Malerba G, Pignatti PF . A review of asthma genetics: gene expression studies and recent candidates . Journal of Applied Genetics . 46 . 1 . 93–104 . 2005 . 15741670 .
• Vassilatis DK, Hohmann JG, Zeng H, Li F, Ranchalis JE, Mortrud MT, Brown A, Rodriguez SS, Weller JR, Wright AC, Bergmann JE, Gaitanaris GA . The G protein-coupled receptor repertoires of human and mouse . Proceedings of the National Academy of Sciences of the United States of America . 100 . 8 . 4903–8 . Apr 2003 . 12679517 . 153653 . 10.1073/pnas.0230374100 . 2003PNAS..100.4903V . free .
• Gupte J, Cutler G, Chen JL, Tian H . Elucidation of signaling properties of vasopressin receptor-related receptor 1 by using the chimeric receptor approach . Proceedings of the National Academy of Sciences of the United States of America . 101 . 6 . 1508–13 . Feb 2004 . 14757815 . 341764 . 10.1073/pnas.0308250100 . 2004PNAS..101.1508G . free .
• Laitinen T, Polvi A, Rydman P, Vendelin J, Pulkkinen V, Salmikangas P, Mäkelä S, Rehn M, Pirskanen A, Rautanen A, Zucchelli M, Gullstén H, Leino M, Alenius H, Petäys T, Haahtela T, Laitinen A, Laprise C, Hudson TJ, Laitinen LA, Kere J . Characterization of a common susceptibility locus for asthma-related traits . Science . 304 . 5668 . 300–4 . Apr 2004 . 15073379 . 10.1126/science.1090010 . 2004Sci...304..300L . 9149671 .
• Xu YL, Reinscheid RK, Huitron-Resendiz S, Clark SD, Wang Z, Lin SH, Brucher FA, Zeng J, Ly NK, Henriksen SJ, de Lecea L, Civelli O . Neuropeptide S: a neuropeptide promoting arousal and anxiolytic-like effects . Neuron . 43 . 4 . 487–97 . Aug 2004 . 15312648 . 10.1016/j.neuron.2004.08.005 . 15601843 . free .
• Melén E, Bruce S, Doekes G, Kabesch M, Laitinen T, Lauener R, Lindgren CM, Riedler J, Scheynius A, van Hage-Hamsten M, Kere J, Pershagen G, Wickman M, Nyberg F . Haplotypes of G protein-coupled receptor 154 are associated with childhood allergy and asthma . American Journal of Respiratory and Critical Care Medicine . 171 . 10 . 1089–95 . May 2005 . 15710598 . 10.1164/rccm.200410-1317OC .
• Kormann MS, Carr D, Klopp N, Illig T, Leupold W, Fritzsch C, Weiland SK, von Mutius E, Kabesch M . G-Protein-coupled receptor polymorphisms are associated with asthma in a large German population . American Journal of Respiratory and Critical Care Medicine . 171 . 12 . 1358–62 . Jun 2005 . 15764725 . 10.1164/rccm.200410-1312OC .
• Gloriam DE, Schiöth HB, Fredriksson R . Nine new human Rhodopsin family G-protein coupled receptors: identification, sequence characterisation and evolutionary relationship . Biochimica et Biophysica Acta (BBA) - General Subjects . 1722 . 3 . 235–46 . Apr 2005 . 15777626 . 10.1016/j.bbagen.2004.12.001 .
• Postma DS, Koppelman GH . Confirmation of GPRA: a putative drug target for asthma . American Journal of Respiratory and Critical Care Medicine . 171 . 12 . 1323–4 . Jun 2005 . 15941840 . 10.1164/rccm.2503006 .
• Vendelin J, Pulkkinen V, Rehn M, Pirskanen A, Räisänen-Sokolowski A, Laitinen A, Laitinen LA, Kere J, Laitinen T . Characterization of GPRA, a novel G protein-coupled receptor related to asthma . American Journal of Respiratory Cell and Molecular Biology . 33 . 3 . 262–70 . Sep 2005 . 15947423 . 10.1165/rcmb.2004-0405OC .
• Söderhäll C, Marenholz I, Nickel R, Grüber C, Kehrt R, Rohde K, Griffioen RW, Meglio P, Tarani L, Gustafsson D, Hoffmann U, Gerstner B, Müller S, Wahn U, Lee YA . Lack of association of the G protein-coupled receptor for asthma susceptibility gene with atopic dermatitis . The Journal of Allergy and Clinical Immunology . 116 . 1 . 220–1 . Jul 2005 . 15990798 . 10.1016/j.jaci.2005.03.002 . 11573/114973 .
• Veal CD, Reynolds NJ, Meggitt SJ, Allen MH, Lindgren CM, Kere J, Trembath RC, Barker JN . Absence of association between asthma and high serum immunoglobulin E associated GPRA haplotypes and adult atopic dermatitis . The Journal of Investigative Dermatology . 125 . 2 . 399–401 . Aug 2005 . 16098057 . 10.1111/j.0022-202X.2005.23828.x . free .
• Feng Y, Hong X, Wang L, Jiang S, Chen C, Wang B, Yang J, Fang Z, Zang T, Xu X, Xu X . G protein-coupled receptor 154 gene polymorphism is associated with airway hyperresponsiveness to methacholine in a Chinese population . The Journal of Allergy and Clinical Immunology . 117 . 3 . 612–7 . Mar 2006 . 16522461 . 10.1016/j.jaci.2005.11.045 . free .
• Bernier V, Stocco R, Bogusky MJ, Joyce JG, Parachoniak C, Grenier K, Arget M, Mathieu MC, O'Neill GP, Slipetz D, Crackower MA, Tan CM, Therien AG . Structure-function relationships in the neuropeptide S receptor: molecular consequences of the asthma-associated mutation N107I . The Journal of Biological Chemistry . 281 . 34 . 24704–12 . Aug 2006 . 16790440 . 10.1074/jbc.M603691200 . free .
• Allen IC, Pace AJ, Jania LA, Ledford JG, Latour AM, Snouwaert JN, Bernier V, Stocco R, Therien AG, Koller BH . Expression and function of NPSR1/GPRA in the lung before and after induction of asthma-like disease . American Journal of Physiology. Lung Cellular and Molecular Physiology . 291 . 5 . L1005-17 . Nov 2006 . 16829631 . 10.1152/ajplung.00174.2006 . 5888233 .
• Vendelin J, Bruce S, Holopainen P, Pulkkinen V, Rytilä P, Pirskanen A, Rehn M, Laitinen T, Laitinen LA, Haahtela T, Saarialho-Kere U, Laitinen A, Kere J . Downstream target genes of the neuropeptide S-NPSR1 pathway . Human Molecular Genetics . 15 . 19 . 2923–35 . Oct 2006 . 16926187 . 10.1093/hmg/ddl234 . free .
• Pulkkinen V, Haataja R, Hannelius U, Helve O, Pitkänen OM, Karikoski R, Rehn M, Marttila R, Lindgren CM, Hästbacka J, Andersson S, Kere J, Hallman M, Laitinen T . G protein-coupled receptor for asthma susceptibility associates with respiratory distress syndrome . Annals of Medicine . 38 . 5 . 357–66 . 2007 . 16938805 . 10.1080/07853890600756453 . 10090669 .

External links

• Web site: Neuropeptide S Receptor . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology . 2007-11-03 . 2016-02-06 . https://web.archive.org/web/20160206040445/http://www.iuphar-db.org/GPCR/ChapterMenuForward?chapterID=1324 . dead .

Notes and References

1. Vassilatis DK, Hohmann JG, Zeng H, Li F, Ranchalis JE, Mortrud MT, Brown A, Rodriguez SS, Weller JR, Wright AC, Bergmann JE, Gaitanaris GA . The G protein-coupled receptor repertoires of human and mouse . Proceedings of the National Academy of Sciences of the United States of America . 100 . 8 . 4903–8 . Apr 2003 . 12679517 . 153653 . 10.1073/pnas.0230374100 . 2003PNAS..100.4903V . free .
2. Vendelin J, Pulkkinen V, Rehn M, Pirskanen A, Räisänen-Sokolowski A, Laitinen A, Laitinen LA, Kere J, Laitinen T . Characterization of GPRA, a novel G protein-coupled receptor related to asthma . American Journal of Respiratory Cell and Molecular Biology . 33 . 3 . 262–70 . Sep 2005 . 15947423 . 10.1165/rcmb.2004-0405OC .
3. Web site: Entrez Gene: NPSR1 neuropeptide S receptor 1.
4. Xu YL, Reinscheid RK, Huitron-Resendiz S, Clark SD, Wang Z, Lin SH, Brucher FA, Zeng J, Ly NK, Henriksen SJ, de Lecea L, Civelli O . Neuropeptide S: a neuropeptide promoting arousal and anxiolytic-like effects . Neuron . 43 . 4 . 487–97 . Aug 2004 . 15312648 . 10.1016/j.neuron.2004.08.005 . 15601843 . free .
5. Okamura N, Reinscheid RK . Neuropeptide S: a novel modulator of stress and arousal . Stress . 10 . 3 . 221–6 . Aug 2007 . 17613937 . 10.1080/10253890701248673 . 39068808 .
6. Laitinen T, Polvi A, Rydman P, Vendelin J, Pulkkinen V, Salmikangas P, Mäkelä S, Rehn M, Pirskanen A, Rautanen A, Zucchelli M, Gullstén H, Leino M, Alenius H, Petäys T, Haahtela T, Laitinen A, Laprise C, Hudson TJ, Laitinen LA, Kere J . Characterization of a common susceptibility locus for asthma-related traits . Science . 304 . 5668 . 300–4 . Apr 2004 . 15073379 . 10.1126/science.1090010 . 2004Sci...304..300L . 9149671 .
7. Vendelin J, Bruce S, Holopainen P, Pulkkinen V, Rytilä P, Pirskanen A, Rehn M, Laitinen T, Laitinen LA, Haahtela T, Saarialho-Kere U, Laitinen A, Kere J . Downstream target genes of the neuropeptide S-NPSR1 pathway . Human Molecular Genetics . 15 . 19 . 2923–35 . Oct 2006 . 16926187 . 10.1093/hmg/ddl234 . free .
8. Wan Saudi WS, Halim MA, Rudholm-Feldreich T, Gillberg L, Rosenqvist E, Tengholm A, Sundbom M, Karlbom U, Näslund E, Webb DL, Sjöblom M, Hellström PM . Neuropeptide S inhibits gastrointestinal motility and increases mucosal permeability through nitric oxide . Am J Physiol Gastrointest Liver Physiol . 309 . 9 . G625-34 . Oct 2015 . 26206857 . 10.1152/ajpgi.00104.2015 . free .
9. Xing L, Shi G, Mostovoy Y, Gentry NW, Fan Z, McMahon TB, Kwok PY, Jones CR, Ptáček LJ, Fu YH . Mutant neuropeptide S receptor reduces sleep duration with preserved memory consolidation . Science Translational Medicine . 11 . 514 . eaax2014 . October 2019 . 31619542 . 7587149 . 10.1126/scitranslmed.aax2014 . 204756335 .
10. Weedon MN, Jones SE, Lane JM, Lee J, Ollila HM, Dawes A, Tyrrell J, Beaumont RN, Partonen T, Merikanto I, Rich SS, Rotter JI, Frayling TM, Rutter MK, Redline S, Sofer T, Saxena R, Wood AR . The impact of Mendelian sleep and circadian genetic variants in a population setting . PLoS Genetics . 18 . 9 . e1010356 . September 2022 . 36137075 . 9499244 . 10.1371/journal.pgen.1010356 . free .