Cellular Physiology Cell Physiol Biochem 2018;45:88-107 DOI: 10.1159/00048622510.1159/000486225 © 2018 The Author(s).© 2018 Published The Author(s) by S. Karger AG, Basel Published online: online: January January 08, 08, 2018 2018 www.karger.com/cpbPublished by S. Karger AG, Basel 88 and Biochemistry www.karger.com/cpb Yi et al.: NPY Receptors in Metabolic Diseases Accepted: October 17, 2017 This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 Interna- tional License (CC BY-NC-ND) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission. Review A Promising Therapeutic Target for Metabolic Diseases: Neuropeptide Y Receptors in Humans Min Yia,b,c Hekai Lia,b,c Zhiye Wua,b,c Jianyun Yana,b,c Qicai Liua,b,c Caiwen Oua,b,c Minsheng Chena,b,c aDepartment of Cardiology, Heart Center, Zhujiang Hospital, Southern Medical University; Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University; bGuangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease; cSino-Japanese Cooperation Platform for Translational Research in Heart Failure, Guangzhou, P. R. China Key Words Neuropeptide Y • Neuropeptide Y receptors • G-protein-coupled receptors (GPCRs) • Metabolic diseases Abstract Human neuropeptide Y (hNPY) is one of the most widely expressed neurotransmitters in the human central and peripheral nervous systems. It consists of 36 highly conserved amino acid residues, and was first isolated from the porcine hypothalamus in 1982. While it is the most recently discovered member of the pancreatic polypeptide family (which includes neuropeptide Y, gut-derived hormone peptide YY, and pancreatic polypeptide), NPY is the most abundant peptide found in the mammalian brain. In order to exert particular functions, NPY needs to bind to the NPY receptor to activate specific signaling pathways. NPY receptors belong to the class A or rhodopsin-like G-protein coupled receptor (GPCR) family and signal via cell-surface receptors. By binding to GPCRs, NPY plays a crucial role in various biological processes, including cortical excitability, stress response, food intake, circadian rhythms, and cardiovascular function. Abnormal regulation of NPY is involved in the development of a wide range of diseases, including obesity, hypertension, atherosclerosis, epilepsy, metabolic disorders, and many cancers. Thus far, five receptors have been cloned from mammals (Y1, Y2, Y4, Y5, and y6), but only four of these (hY1, hY2, hY4, and hY5) are functional in humans. In this review, we summarize the structural characteristics of human NPY receptors and their role in metabolic diseases. © 2018 The Author(s) Published by S. Karger AG, Basel Introduction Neuropeptide Y is widely expressed in the human central and peripheral nervous sys- tem. This is a highly conserved 36-amino acid peptide which was first isolated from porcine Minsheng Chen Laboratory of Heart Center, Zhujiang hospital, Southern Medical University, andhypothalamus Caiwen Ou in 1982 [1]. ThereNo.1023,Shatai are three Nan members Road, Guangzhou of the (China); pancreatic Tel.+8613825199222, polypeptide +8618902309513, family, E-Mail [email protected], [email protected] Cellular Physiology Cell Physiol Biochem 2018;45:88-107 DOI: 10.1159/000486225 © 2018 The Author(s). Published by S. Karger AG, Basel and Biochemistry Published online: January 08, 2018 www.karger.com/cpb 89 Yi et al.: NPY Receptors in Metabolic Diseases - namely the neuropeptide Y, the gut-derived hormone peptide YY (PYY) and pancreatic poly- peptide (PP). Endogenous ligands (usually NPY, PYY and PP) and their C-terminal segments, monomerespecially proteinsthose with and parent belong residues to the class 3-36 A and or rhodopsin-like 13-36 [2, 3] activate G-protein Y receptors coupled receptorsvia bind ing and triggering a conformational change of the Y0 receptors (Table 1). NPY receptors are (GPCRs) [4]. After binding to the ligands, the Gi or G subunit of the heterotrimeric G protein- complex is released2+ and and K in+ turn leads to the inhibition of adenylate cyclase, which prevents tothe the conversion Gi or G0 of ATP to the second signaling molecule, cAMP [4]. Finally, cAMP levels are re duced and the Ca channels are modulated [5]. Generally, NPY receptors are coupled- subunit. In rabbit smooth muscle cells, it has also been reported that Y2 and Y4- receptors could bind to the Gq protein and+ promote2+ the production of inositol 1, 4,5-triphos phate (IP3) by activating phospholipase C-β (PLC) [6]. In rat arcuate neurons, it was report- ed that NPY receptors could regulate K and Ca channels, and G protein-coupled inwardly Tablerectifying 1. potassium channels (Fig. 1) [4]. In addition to the seven membrane-confined he The Characteristics of NPY Receptors In Humans The characteristics of NPY receptors in humans NPY receptor Y1 [140] NPY receptor Y2 [141] NPY receptor Y4 [142] NPY receptor Y5 [143] Amino acids 384 381 375 445-455 Expression Periphery, Brain, hippocampus, thalamus, Brain, gastrointestinal tract, Hypothalamus, hippocampus hypothalamus, hypothalamus pancreas, prostate hippocampus, neocortex, thalamus Sequence of pNPY YPSKPDNPGEDAPAEDLARYYSALRHYINLITRQRY ligand hPYY YPIKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY structure hPP APLEPVYPGDNATPEQMAQYAADLRRYINMLTRPRY Agonists NPY (endogenous NPY (endogenous agonist); NPY PP; NPY (endogenous agonist, NPY (endogenous agonist); agonist, non-subtype fragment 13-36(selective); 2- non-subtype selective); PYY; BWX-46 (selective NPY5 selective); PYY Thiouridine 5'triphosphate; PYY; PYY 3- GR-231,118 (mixed NPY1 agonist); PYY 36 fragment antagonist / NPY4 agonist) Antagonists 1.Peptide: BVD-10 BIIE-0246 [5, 37, 144, 145], JNJ UR-AK49 CGP-71683, FMS-586 [6],L- (selective NPY1 5207787 ,SF 11 152,804,Lu AA-33810 [7],MK- antagonist), GR-231,118 0557 [8], NTNCB [9], (mixed NPY1 antagonist Velneperit / NPY4 agonist) 2.Non-peptide: BIBO- 3304,BIBP-3226,PD- 160,170 Location Chr 4: 163.32 – 163.34 Chr 4: 155.21 – 155.22 Mb Chr 10: 46.46 – 46.47 Mb Chr 4: 163.34 – 163.35 Mb Mb Function vasoconstriction, Memory, circadian rhythm, Feeding, circadian ingestion, Food intake, epilepsy, circadian anxiolysis, food intake, angiogenesis, epilepsy, secretion, bone energy homeostasis, colonic rhythm heart rate, anxiety formation transit Molecular NPY receptor /GPCR/Signal transduction function protein binding; PYY/ protein binding; PYY/PP receptor PP receptor PYY/PP receptor PP receptor calcium channel regulation Biological GPCR/AC-inhibiting GPCR/cell surface receptor /AC- GPCR/cell surface GPCR/cell surface receptor/ process GPCR/cell surface inhibiting GPCR/dopamine secretion/ receptor/neuropeptide neuropeptide signaling receptor/ neuropeptide neuropeptide signaling pathways signaling pathways pathway signaling pathways positive regulation of cytosolic calcium blood circulation positive regulation of acute locomotory behavior ion concentration/peptide secretion feeding behavior inflammatory response/cell regulation of and circadian sleep/wake cycle, non- digestion and smooth muscle multicellular organism REM sleep/ smooth muscle contraction/ proliferation/ERK1 and ERK2 growth/blood pressure cell-substrate adhesion cascade outflow tract negative regulation of neurological negative regulation of morphogenesis system process/synaptic glutamate secretion/apoptotic blood circulation transmission/excitatory postsynaptic process/synaptic transmission, feeding behavior potential/ secretion/ feeding GABAergic/acute inflammatory glucose metabolic behavior/cAMP biosynthetic response to antigenic stimulus process process/synaptic transmission, generation of ovulation cycle sensory perception of glutamatergic rhythm pain sensory perception of pain eating/feeding behavior locomotory/feeding behavior outflow tract morphogenesis outflow tract morphogenesis aging cardiac left ventricle morphogenesis cardiac left ventricle behavioral fear response morphogenesis nitric oxide mediated signal chemical synaptic transmission transduction aging chemical synaptic transmission Cellular Physiology Cell Physiol Biochem 2018;45:88-107 DOI: 10.1159/000486225 © 2018 The Author(s). Published by S. Karger AG, Basel and Biochemistry Published online: January 08, 2018 www.karger.com/cpb 90 Yi et al.: NPY Receptors in Metabolic Diseases lices, the heptahelical GPCRs have four extracellular and four intracellular segments, which- could be labeled as ec1-ec4 and ic1-ic4, respectively. The ec1 is an extracellular N-terminus and the ic4 is a intracellular C-terminus which cloud anchor onto the membrane by palmi toylation. The other six segments form three extracellular loops I-III and intracellular loops I-III was formed by the ec2-ec4 and ic1-ic3 segments, respectively. In extracellular regions, a disulfide bond between ec2 and ec3 segments is formed by two highly conserved cysteine (Cys) residues. This disulfide bond is a general feature of class A GPCRs and has been related to the stability of these receptors [7, 8]. The extracellular parts of the receptor can also be modified by glycosylation. In the intracellular regions, the C terminal tail, namely the ic4 ansegment, elementary and the complex ic2 segment coupled form to Y tworeceptors G protein [9]. binding sites. These two helices interact with signal transduction protein GTPases and bind to G proteins which consequently form Thus far, seven different Y receptors (Y1-Y8) have been