Elsevier

Peptides

Volume 18, Issue 3, 1997, Pages 445-457
Peptides

Review
Neuropeptide Y Family of Hormones: Receptor Subtypes and Antagonists

https://doi.org/10.1016/S0196-9781(96)00347-6Get rights and content

Abstract

Balasubramaniam, A. Neuropeptide Y family of hormones: Receptor subtypes and antagonists. Peptides 18(3) 445–457, 1997.—Neuropeptide Y (NPY) is the most abundant peptide present in the mammalian central and peripheral nervous system. NPY exhibits a variety of potent central and peripheral effects including those on feeding, memory, blood pressure, cardiac contractility and intestinal secretions. Classical pharmacological studies have shown that NPY effects are mediated by four different receptor subtypes, Y-1, Y-1-like, Y-2, and Y-3. However, the existence of numerous atypical activities provide strong evidence for the occurrence of additional NPY receptor subtypes. Pharmacological studies have further been facilitated by the recent cloning and expression of Y-1, Y-2, Y-4 (PP-1) and Y-5 receptors. Moreover, the cloned Y-5 receptor has been suggested to be the long awaited Y-1-like receptor involved in feeding. Structure-activity studies have laid a good foundation towards the development of receptor selective compounds, and to date potent Y-1 selective peptide and nonpeptide antagonists have been developed. The need to clone numerous receptor subtypes and to develop receptor selective compounds for physiological and perhaps clinical use is expected to keep NPY research active for many years to come.

Section snippets

Isolation and Structure

NPY is a 36-residue peptide amide isolated initially from porcine brain 139, 140. NPY has also been isolated from species at various levels in the phylogenetic tree which shows that the primary structure of NPY has been rigidly conserved through evolution [86]. Previously, Tatemoto [138] isolated an NPY-like peptide from porcine intestine and termed it peptide YY (PYY). NPY and PYY exhibit 70% homology between each other, and about 50% with pancreatic polypeptide (PP) [82]. Isolation of cDNAs

Distribution

NPY is considered to be the most abundant and widely distributed neuropeptide present in the mammalian central and peripheral nervous system. In the periphery, it is generally found in the sympathetic nervous system, co-stored and co-released with norepinephrine 73, 89, 98, 136. However, NPY has also been found in nonsympathetic neurons in several organs including gastrointestinal tract, salivary glands, thyroid gland, pancreas, urinogenital system, airways and heart [137].

The distribution of

1. Actions and Receptor Subtypes

The abundance of NPY in brain and in the nerve fibers around the blood vessels, heart and gastrointestinal tract attracted numerous investigations as to the role of NPY in these organs. These studies, discussed in detail below, demonstrated that NPY plays a major role in controlling appetite, blood pressor, cardiac contractility and intestinal secretion.

2. Cloned NPY Receptors

All the NPY family of receptors cloned to date have the putative seven transmembrane domains characteristic of the G-protein coupled superfamily of receptors (Table 2). Li et. al. [91] reported the first cloning of a NPY receptor from Drosophila melanogaster. When expressed in oocytes, NPY related peptides activated inward currents characteristic of IP3-coupled agonists with an unusual order of potency: PYY > C2-NPY (a centrally truncated cyclic analog) > NPY > [Pro34]NPY. This observation and

3. NPY Receptor Antagonists

The existence of NPY receptor heterogeneity suggests that it is possible to dissociate the effects of NPY and design analogs with properties for interaction with only selected receptor subtypes. This observation, and the finding that NPY analogs may have clinical utility, attracted numerous scientists to design ligands for selected receptor subtypes. Table 3 summarizes the properties of the antagonists reported to date.

Our efforts towards designing NPY receptor antagonists resulted in the

Note Added in Proof

Recent investigations have shown that BIBP3226 could also antagonize NPY-induced feeding in rats (Pitler et al.; Society for Neuroscience Abstracts, 184.9; 1996).

Acknowledgements

Supported in part by grants from NIH (GM47122) and Biomeasure, Inc., Milford, MA. I am grateful to Professor Josef E. Fischer (Chairman, Department of Surgery, University of Cincinnati) for his continued support and encouragement, Professor Richard Murphy (Chairman, Department of Biomedical Sciences, Creighton University) for introducing me to this field, and many of my collaborators including Dr. William T. Chance and Dr. Sulaiman Sheriff (Department of Surgery, University of Cincinnati) , Dr.

References (162)

  • R.A. Barraco et al.

    Cardiorespiratory response patterns elicited by microinjections of neuropeptide Y in the nucleus tractus solitarius

    Brain Res. Bull.

    (1990)
  • B. Beck et al.

    Putative neuropeptide Y antagonist failed to decrease overeating in obese Zucker rats

    Neurosci. Lett.

    (1994)
  • G. Bottcher et al.

    Peptide YY: A neuropeptide in the gut. Immunocytochemical and Immunochemical Evidence

    Neuroscience

    (1993)
  • P. Broqua et al.

    Antinocieceptive effects of neuropeptide Y and related peptides in mice

    Brain Res.

    (1996)
  • W.T. Chance et al.

    Pertussis toxin inhibits neuropeptide Y-induced feeding in rats

    Peptides

    (1989)
  • W.T. Chance et al.

    Preservation of intestine protein by peptide YY during total parenteral nutrition

    Life Sci.

    (1996)
  • W.F. Colmers et al.

    Effects of neuropeptide Y on the electrical properties of neurons

    Trends in Neurosciences

    (1994)
  • M.B. Doughty et al.

    Benextramine: A long-lasting neuropeptide Y receptor antagonist

    Eur. J. Pharm.

    (1990)
  • Y. Dumont et al.

    Differential distribution of neuropeptide Y1 and Y2 receptors in the rat brain

    Eur. J. Pharmacol.

    (1990)
  • L. Edvinsson et al.

    Neuropeptide Y antagonistic properties of D-myo-inositol-1.2.6-trisphosphate in guinea pig basilar arteries

    Neuropeptides

    (1990)
  • R. Ekman et al.

    Peptide YY-like immunoreactivity in the central nervous system of the rat: Occurrence, distribution and partial characterization

    Regul. Pept.

    (1986)
  • C. Eva et al.

    Molecular cloning of a novel G protein-coupled receptor that may belong to the neuropeptide receptor family

    FEBS Lett.

    (1990)
  • H.M. Frankish et al.

    Neuropeptide Y, the hypothalamus, diabetes: Insights into the central control of metabolism

    Peptides

    (1995)
  • J. Fuhlendorff et al.

    The antiparallel pancreatic polypeptide fold in the binding of neuropeptide Y to Y1 and Y2 receptors

    J. Biol. Chem.

    (1990)
  • C. Gerald et al.

    Expression cloning and pharmacological characterization of human hippocampal neuropeptide Y/peptide YY Y2 receptor subtype

    J. Biol. Chem.

    (1995)
  • P. Gregor et al.

    Cloning and characterization of a novel receptor to pancreatic polypeptide, a member of the neuropeptide Y receptor family

    FEBS Lett.

    (1996)
  • L. Grundemar et al.

    Neuropeptide Y effector systems: Perspectives for drug development

    Trends Pharmacol. Sci.

    (1994)
  • L. Grundemar et al.

    Biphasic blood pressure response to neuropeptide Y in anesthetized rats

    Eur. J. Pharmacol.

    (1990)
  • M. Heilig et al.

    Corticotropin-releasing factor and neuropeptide Y: Role in emotional integration

    Trends Neurosci.

    (1994)
  • J. Hinson et al.

    Neuropeptide Y stimulates inositol phospholipid hydrolysis in rat brain miniprisms

    Brain Res.

    (1988)
  • Y. Hu et al.

    Identification of a novel hypothalamic neuropeptide Y receptor associated with feeding behavior

    J. Biol. Chem.

    (1996)
  • E.E. Jazin et al.

    A proposed bovine neuropeptide Y (NPY) receptor cDNA clone, or its human homologue, confers neither NPY binding sites nor NPY responsiveness on transfected cells

    Regul. Pept.

    (1993)
  • S.P. Kalra et al.

    Structure-function analysis of stimulation of food intake by neuropeptide Y: Effects of receptor agonists

    Physiol. Behav.

    (1991)
  • S. Kassis et al.

    Neuropeptide Y inhibits cardiac adenylate cyclase through a pertussis toxin-sensitive G protein

    J. Biol. Chem.

    (1987)
  • J.R. Kimmel et al.

    Isolation and characterization of a new pancreatic polypeptide hormone

    J. Biol. Chem.

    (1975)
  • D. Larhammar et al.

    Cloning and Functional Expression of a Human Neuropeptide Y/Peptide YY Receptor of the Y1 Type

    J. Biol. Chem.

    (1992)
  • X-J. Li et al.

    Cloning, functional expression and developmental regulation of neuropeptide Y receptor from Drosophila melanogaster

    J. Biol. Chem.

    (1992)
  • J.M. Lundberg et al.

    Recent developments with neuropeptide Y receptor antagonists

    Trends Pharmacol. Sci.

    (1996)
  • I. Lundell et al.

    Cloning of a human receptor of the NPY receptor family with high affinity for pancreatic polypeptide and peptide YY

    J. Biol. Chem.

    (1995)
  • K. Arvidsson et al.

    Solution Structure by 2D 1H-NMR of a Chimeric Peptide Recognized by Galanin and Neuropeptide Y Receptors

    Biochemistry

    (1993)
  • A. Balasubramaniam et al.

    Proteins, Structure, Dynamics and Design

  • A. Balasubramaniam et al.

    Synthesis and receptor affinities of partial sequences of peptide YY (PYY)

    Pept. Res.

    (1988)
  • A. Balasubramaniam et al.

    [D-Trp32]neuropeptide Y (NPY): A competitive antagonist of NPY in rat hypothalamus

    J. Med. Chem.

    (1994)
  • A. Balasubramaniam et al.

    High yeild synthesis of pseudopeptide analogs of cardiac NPY receptor antagonist, NPY (18-36)

  • A. Balasubramaniam et al.

    Synthesis and binding properties of PYY (22-36) analogs:Development of a potent proabsorptive peptide

  • A. Balasubramaniam et al.

    Antagonistic Properties of centrally truncated analogs of [D-Trp32]NPY

    J. Med. Chem.

    (1996)
  • A. Balasubramaniam et al.

    Bis (31/31′){Cys31, Trp32, Nva34]NPY- (31-36)}: A Specific NPY-Y-1 Receptor Antagonist

    J. Med. Chem.

    (1996)
  • G.H. Ballantyne et al.

    Inhibition of VIP-stimulated ion transport by a novel Y-receptor phenotype in rabbit distal colon

    Am. J. Physiol.

    (1993)
  • A.G. Beck-Sickinger et al.

    Structure-activity relationships of neuropeptide Y analogs with respect to Y1 and Y2 receptors

    Biopolymers

    (1995)
  • D. Bleakman et al.

    Neuropeptide Y inhibits Ca2+ influx into cultured dorsal root ganglion neurones of the rat via a Y2 receptor

    Br. J. Pharmacol.

    (1991)
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