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Neuropeptide Y Family
CHAPTER 25
Neuropeptide Y Family Yoshio Takei
History The neuropeptide Y family consists of neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP). NPY was first isolated from the porcine brain in 1982 using a chemical assay that permits detection of peptides with C-terminal amidation [1,2]. PYY was isolated from the porcine intestine, using the same methodology, in 1982. PP was discovered earlier, in 1968, as a byproduct of insulin isolation from the chicken pancreas, and its sequence was determined in 1975. Since then, NPY family members have been identified in various vertebrate species as a peptide or a cDNA. NPY and PYY are found from cyclostomes (lampreys) to mammals, but PP is identifiable only in tetrapods, including amphibians, reptiles, birds, and mammals [2].
Structure Structural Features All members of the NPY family consist of 36 aa residues with an amidated C-terminus. NPY and PYY have tyrosine (Y) residues at both termini, which is the origin of their names. NPY has the highest sequence identity (only 1 aa different between human and chicken), followed by PYY, and PP is the most variable peptide even in mammals. Fish PYYs are equally similar to mammalian NPY and PYY, but they are distinguishable by proline at position 14, where NPY has alanine in all species (Figure 25.1). The common structural feature is the presence of a “PP-fold,” characterized by the helix structure with three intermittent proline residues and that with two tyrosine residues facing each other following an abrupt turn [1]. The N-terminal dipeptide of PYY is readily cleaved by dipeptidyl peptidase 4 (EC 3.4.14.5) to produce PYY3 36, which is a major circulating form in the blood [3].
Molecular Evolution of Family Members It appears that NPY and PYY existed in ancestral vertebrates, as both have been identified in the most primitive extant jawless vertebrates, cyclostomes. The NPY and PYY genes in human (NPY and PYY) and npy and pyy in zebrafish are linked to a hox gene, indicating that the two genes are the products of whole genome duplication. Another PYY, named PYY2, has been found in ungulates and primates, but only bovine seminal plasmin seems to be a functional peptide produced from the PYY2 gene. The additional whole genome duplication that occurred only in the teleost lineage may have produced two NPY genes (npya and npyb) and two PYY
genes (pyya and pyyb). Judging from the CNS localization and the highest sequence conservation, NPY may retain characteristics of the ancestral molecule. It is not known whether the NPY family genes originated from chordates or exist in protostomes. The PP gene may be generated by tandem duplication of the PYY gene after divergence of ray-finned fishes and lobe-finned fishes, as both genes exist on the same chromosome and PP was found only in tetrapods. It is not yet known whether the PP gene exists in lobe-finned fishes.
Receptors Structure and Subtypes At least five types of receptors, named Y receptors, have been identified for NPY family peptides in mammals: Y1, Y2, Y4, Y5, and Y6 [4,5]. No biological function was assigned to Y6, and it is a pseudogene in human and other tetrapods, so Y6 is often distinguished from other Y receptors by a lower-case letter (y6). The presence of Y3 is suggested only by pharmacological evidence. Additional Y receptors, Yb and Y7, were found in zebrafish and other teleosts, and frogs seem to retain Y7. Y1 and Y5, important receptors of NPY for appetite arousal, are lost in teleosts. The ancestral Y receptors may have existed as three subfamilies (Y1, Y2, and Y5), and they are generated by tandem duplication on the same chromosome in primitive vertebrates, as at least Y1 and Y2 already existed in lampreys. Because of their ancient origin, sequence identity of the three subfamily receptors is low (B30%) compared with those of other GPCRs that share the same ligand. It seems that some Y receptor genes have disappeared in different lineages after whole genome duplications. Y4, Y6, and Yb are classified as the Y1 subfamily, and Y2 and Y7 are grouped as the Y2 subfamily. NPY and PYY exhibit similar high affinities for Y1, Y2, and Y5 subfamily receptors, while PP preferentially binds to Y4 of the Y1 subfamily, and, interestingly, NPY3 36 and PYY3 36 are preferred ligands for the Y2 subfamily receptors. In the brain, the Y1 and Y2 genes are ubiquitously expressed in various regions, but the expression of Y4 and Y5 genes is restricted to specific loci involved in the regulation of appetite, circadian rhythm, and anxiety.
Signal Transduction Pathway The Y receptors belong to the GPCRs that couple to pertussis toxin-sensitive Gi/o protein [6]. Thus, the NPY family peptides basically exhibit their function through inhibition of the cAMP dependent kinase (A-kinase).
Y. Takei, H. Ando, & K. Tsutsui (Eds): Handbook of Hormones. DOI: http://dx.doi.org/10.1016/B978-0-12-801028-0.00025-8 © 2016 Elsevier Inc. All rights reserved.
211
P A R T I Peptides and Proteins in Vertebrates
Figure 25.1 Comparison of amino acid sequences of the NPY family in different vertebrate species. Pancreatic polypeptide is absent in fishes. For abbreviations, see text.
Biological Functions Target Cells/Tissues and Functions The NPY family constitutes important members of the brain gut hormones, which play pivotal roles in neural and humoral communication between the digestive tract and the CNS (gut brain axis) [4,7]. NPY is basically a neuropeptide synthesized in the CNS, enteric neurons, and primary afferent neurons, and acts locally in the brain to regulate food intake, energy metabolism, anxiety, cognition, stress resilience, and nociception, and in the gastrointestinal tract to regulate its function via Y1, Y2, and Y5 subfamily receptors [4]. By contrast, PYY and PP are gastrointestinal hormones, and their synthesis in the brain is minimal. PYY is secreted from the intestinal L cells and PP from the pancreatic F cells; this is stimulated following a meal. NPY and PYY act in a paracrine fashion in the gastrointestinal tract to inhibit their motility and electrolyte secretion from crypt cells, which is in contrast to the stimulatory actions by various hormones, including vasoactive intestinal peptide, natriuretic peptides, and guanylin [8]. PYY co-localizes with proglucagon-derived peptides, suggesting a synergistic action on insulin secretion. The main action of PP is to inhibit exocrine secretions from the pancreas and gall bladder. The most prominent action of NPY is an enhancement of food intake (see Chapter 10), but NPY gene knockout did not resulted in reduced food intake. Interestingly, NPY induces appetite but PYY and PP inhibit it,
212
although both NPY and PYY bind to Y1 and Y5 with high affinities. It seems that PYY is cleaved to PYY3 36 immediately and acts on Y2. The expression of the PP gene is scarce in the brain, but its receptor (Y4) knockout resulted in reduced anxiety and depression [9]. References 1. Conlon MJ. The origin and evolution of peptide YY (PYY) and pancreatic polypeptide (PP). Peptides. 2002;23:269 278. 2. Larhammer D. Evolution of neuropeptide Y, peptide YY and pancreatic polypeptide. Reg Pept. 1996;62:1 11. 3. Medeiros MD, Turner AJ. Processing and metabolism of peptideYY: pivotal roles of dipeptidylpeptidase-IV, aminopeptidase-P, and endopeptidase-24.11. Endocrinology. 1994;134:2088 2094. 4. Holzer P, Reichmann F, Farzi A, Neuropeptide Y. peptide YY and pancreatic polypeptide in the gut brain axis. Neuropeptides. 2012;46:261 274. 5. Larhammer D, Salaneck E. Molecular evolution of NPY peptide subtypes. Neuropeptides. 2004;38:141 151. 6. Alexander SPH, Mathie A, Peters JA. G protein-coupled receptors.. Br J Pharmacol. 2011;164:S5 S113. 7. Field BCT, Chaudhri OB, Bloom SR. Bowels control brain: gut hormones and obesity. Nat Rev Endocrinol. 2010;6:444 453. 8. Cox HM. Neuropeptide Y receptors; antisecretory control of intestinal epithelial function. Auton Neurosci. 2007;133:76 85. 9. Painsipp E, Wultsch T, Edelsbrunner ME, et al. Reduced anxietylike and depression-related behavior in neuropeptide Y Y4 receptor knockout mice. Genes Brain Behav. 2008;7:532 542.
C H A P T E R 2 5 Neuropeptide Y Family Supplemental Information
hNPY SP
NPY
1k
4.1 k
2.1 k
hPYY SP
PYY
366
106
128
hPP SP 766
PP 249
190
100 bp coding region mature peptide non-coding region SP: signal peptide
E-Figure 25.1 Gene structures of human neuropeptide Y (NPY), peptide tyrosine tyrosine (PYY), and pancreatic polypeptide (PP). Boxes show exons.
NPYR NPY4R
NPY1R
NPY Human PP
NPY5R Human PYY
NPY2R Chicken PP Xenopus PYY
Elephant shark NPY
Elephant shark PYY Eel PYY Sturgeon PYY
Eel NPY Human NPY Chicken NPY Xenopus NPY
Lamprey PYY
NPY3R
0.1
E-Figure 25.2 Molecular phylogenetic tree of neuropeptide Y family members (NPY, PYY, and PP) from various vertebrate species using MrBayes. Accession numbers are in the web materials for each peptide.
0.1 E-Figure 25.3 Molecular phylogenetic tree of five NPY family receptors (NPY1R NPY5R) of humans using MrBayes. Accession numbers are in the web materials for each ligand.
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Neuropeptide Y Family Yoshio Takei
History The neuropeptide Y family consists of neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP). NPY was first isolated from the porcine brain in 1982 using a chemical assay that permits detection of peptides with C-terminal amidation [1,2]. PYY was isolated from the porcine intestine, using the same methodology, in 1982. PP was discovered earlier, in 1968, as a byproduct of insulin isolation from the chicken pancreas, and its sequence was determined in 1975. Since then, NPY family members have been identified in various vertebrate species as a peptide or a cDNA. NPY and PYY are found from cyclostomes (lampreys) to mammals, but PP is identifiable only in tetrapods, including amphibians, reptiles, birds, and mammals [2].
Structure Structural Features All members of the NPY family consist of 36 aa residues with an amidated C-terminus. NPY and PYY have tyrosine (Y) residues at both termini, which is the origin of their names. NPY has the highest sequence identity (only 1 aa different between human and chicken), followed by PYY, and PP is the most variable peptide even in mammals. Fish PYYs are equally similar to mammalian NPY and PYY, but they are distinguishable by proline at position 14, where NPY has alanine in all species (Figure 25.1). The common structural feature is the presence of a “PP-fold,” characterized by the helix structure with three intermittent proline residues and that with two tyrosine residues facing each other following an abrupt turn [1]. The N-terminal dipeptide of PYY is readily cleaved by dipeptidyl peptidase 4 (EC 3.4.14.5) to produce PYY3 36, which is a major circulating form in the blood [3].
Molecular Evolution of Family Members It appears that NPY and PYY existed in ancestral vertebrates, as both have been identified in the most primitive extant jawless vertebrates, cyclostomes. The NPY and PYY genes in human (NPY and PYY) and npy and pyy in zebrafish are linked to a hox gene, indicating that the two genes are the products of whole genome duplication. Another PYY, named PYY2, has been found in ungulates and primates, but only bovine seminal plasmin seems to be a functional peptide produced from the PYY2 gene. The additional whole genome duplication that occurred only in the teleost lineage may have produced two NPY genes (npya and npyb) and two PYY
genes (pyya and pyyb). Judging from the CNS localization and the highest sequence conservation, NPY may retain characteristics of the ancestral molecule. It is not known whether the NPY family genes originated from chordates or exist in protostomes. The PP gene may be generated by tandem duplication of the PYY gene after divergence of ray-finned fishes and lobe-finned fishes, as both genes exist on the same chromosome and PP was found only in tetrapods. It is not yet known whether the PP gene exists in lobe-finned fishes.
Receptors Structure and Subtypes At least five types of receptors, named Y receptors, have been identified for NPY family peptides in mammals: Y1, Y2, Y4, Y5, and Y6 [4,5]. No biological function was assigned to Y6, and it is a pseudogene in human and other tetrapods, so Y6 is often distinguished from other Y receptors by a lower-case letter (y6). The presence of Y3 is suggested only by pharmacological evidence. Additional Y receptors, Yb and Y7, were found in zebrafish and other teleosts, and frogs seem to retain Y7. Y1 and Y5, important receptors of NPY for appetite arousal, are lost in teleosts. The ancestral Y receptors may have existed as three subfamilies (Y1, Y2, and Y5), and they are generated by tandem duplication on the same chromosome in primitive vertebrates, as at least Y1 and Y2 already existed in lampreys. Because of their ancient origin, sequence identity of the three subfamily receptors is low (B30%) compared with those of other GPCRs that share the same ligand. It seems that some Y receptor genes have disappeared in different lineages after whole genome duplications. Y4, Y6, and Yb are classified as the Y1 subfamily, and Y2 and Y7 are grouped as the Y2 subfamily. NPY and PYY exhibit similar high affinities for Y1, Y2, and Y5 subfamily receptors, while PP preferentially binds to Y4 of the Y1 subfamily, and, interestingly, NPY3 36 and PYY3 36 are preferred ligands for the Y2 subfamily receptors. In the brain, the Y1 and Y2 genes are ubiquitously expressed in various regions, but the expression of Y4 and Y5 genes is restricted to specific loci involved in the regulation of appetite, circadian rhythm, and anxiety.
Signal Transduction Pathway The Y receptors belong to the GPCRs that couple to pertussis toxin-sensitive Gi/o protein [6]. Thus, the NPY family peptides basically exhibit their function through inhibition of the cAMP dependent kinase (A-kinase).
Y. Takei, H. Ando, & K. Tsutsui (Eds): Handbook of Hormones. DOI: http://dx.doi.org/10.1016/B978-0-12-801028-0.00025-8 © 2016 Elsevier Inc. All rights reserved.
211
P A R T I Peptides and Proteins in Vertebrates
Figure 25.1 Comparison of amino acid sequences of the NPY family in different vertebrate species. Pancreatic polypeptide is absent in fishes. For abbreviations, see text.
Biological Functions Target Cells/Tissues and Functions The NPY family constitutes important members of the brain gut hormones, which play pivotal roles in neural and humoral communication between the digestive tract and the CNS (gut brain axis) [4,7]. NPY is basically a neuropeptide synthesized in the CNS, enteric neurons, and primary afferent neurons, and acts locally in the brain to regulate food intake, energy metabolism, anxiety, cognition, stress resilience, and nociception, and in the gastrointestinal tract to regulate its function via Y1, Y2, and Y5 subfamily receptors [4]. By contrast, PYY and PP are gastrointestinal hormones, and their synthesis in the brain is minimal. PYY is secreted from the intestinal L cells and PP from the pancreatic F cells; this is stimulated following a meal. NPY and PYY act in a paracrine fashion in the gastrointestinal tract to inhibit their motility and electrolyte secretion from crypt cells, which is in contrast to the stimulatory actions by various hormones, including vasoactive intestinal peptide, natriuretic peptides, and guanylin [8]. PYY co-localizes with proglucagon-derived peptides, suggesting a synergistic action on insulin secretion. The main action of PP is to inhibit exocrine secretions from the pancreas and gall bladder. The most prominent action of NPY is an enhancement of food intake (see Chapter 10), but NPY gene knockout did not resulted in reduced food intake. Interestingly, NPY induces appetite but PYY and PP inhibit it,
212
although both NPY and PYY bind to Y1 and Y5 with high affinities. It seems that PYY is cleaved to PYY3 36 immediately and acts on Y2. The expression of the PP gene is scarce in the brain, but its receptor (Y4) knockout resulted in reduced anxiety and depression [9]. References 1. Conlon MJ. The origin and evolution of peptide YY (PYY) and pancreatic polypeptide (PP). Peptides. 2002;23:269 278. 2. Larhammer D. Evolution of neuropeptide Y, peptide YY and pancreatic polypeptide. Reg Pept. 1996;62:1 11. 3. Medeiros MD, Turner AJ. Processing and metabolism of peptideYY: pivotal roles of dipeptidylpeptidase-IV, aminopeptidase-P, and endopeptidase-24.11. Endocrinology. 1994;134:2088 2094. 4. Holzer P, Reichmann F, Farzi A, Neuropeptide Y. peptide YY and pancreatic polypeptide in the gut brain axis. Neuropeptides. 2012;46:261 274. 5. Larhammer D, Salaneck E. Molecular evolution of NPY peptide subtypes. Neuropeptides. 2004;38:141 151. 6. Alexander SPH, Mathie A, Peters JA. G protein-coupled receptors.. Br J Pharmacol. 2011;164:S5 S113. 7. Field BCT, Chaudhri OB, Bloom SR. Bowels control brain: gut hormones and obesity. Nat Rev Endocrinol. 2010;6:444 453. 8. Cox HM. Neuropeptide Y receptors; antisecretory control of intestinal epithelial function. Auton Neurosci. 2007;133:76 85. 9. Painsipp E, Wultsch T, Edelsbrunner ME, et al. Reduced anxietylike and depression-related behavior in neuropeptide Y Y4 receptor knockout mice. Genes Brain Behav. 2008;7:532 542.
C H A P T E R 2 5 Neuropeptide Y Family Supplemental Information
hNPY SP
NPY
1k
4.1 k
2.1 k
hPYY SP
PYY
366
106
128
hPP SP 766
PP 249
190
100 bp coding region mature peptide non-coding region SP: signal peptide
E-Figure 25.1 Gene structures of human neuropeptide Y (NPY), peptide tyrosine tyrosine (PYY), and pancreatic polypeptide (PP). Boxes show exons.
NPYR NPY4R
NPY1R
NPY Human PP
NPY5R Human PYY
NPY2R Chicken PP Xenopus PYY
Elephant shark NPY
Elephant shark PYY Eel PYY Sturgeon PYY
Eel NPY Human NPY Chicken NPY Xenopus NPY
Lamprey PYY
NPY3R
0.1
E-Figure 25.2 Molecular phylogenetic tree of neuropeptide Y family members (NPY, PYY, and PP) from various vertebrate species using MrBayes. Accession numbers are in the web materials for each peptide.
0.1 E-Figure 25.3 Molecular phylogenetic tree of five NPY family receptors (NPY1R NPY5R) of humans using MrBayes. Accession numbers are in the web materials for each ligand.
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