Structural diversity of receptors for neuropeptide Y, peptide YY and pancreatic polypeptide

doi:10.1016/0167-0115(96)00110-3

Regulatory Peptides

Volume 65, Issue 3, 16 September 1996, Pages 165-174

https://doi.org/10.1016/0167-0115(96)00110-3 Get rights and content

Abstract

The NPY (neuropeptide Y) family of neuroendocrine peptides consists of NPY, PYY (peptide YY) and PP (pancreatic polypeptide). Several receptors have been characterized pharmacologically of which three have now been cloned. All three belong to the superfamily of receptors that couple to G proteins and all three cause inhibition of cAMP accumulation. Receptor subtypes Y1 and Y2 bind both NPY and PYY. Surprisingly, Y1 and Y2 share only 31% overall sequence identity, the lowest percentage reported for receptors that bind the same peptide ligand. Nevertheless, each subtype is 94% identical between human and rat, suggesting a slow rate of change. These observations suggest that Y1 and Y2 started to diverge from one another very long ago, possibly before the origin of vertebrates. The PP receptor, called PP1 or Y4, is 42% identical to the Y1 receptor (57% in the transmembrane regions) and is one of the most rapidly evolving receptors with only 75% overall identity between man and rat. Interestingly, this receptor's preferred ligand, PP, also evolves extremely rapidly. The PP receptor also differs between man and rat in tissue distribution and binding properties. The Y1 and PP receptors bind to both termini of their ligands whereas Y2 mainly interacts with the C-terminal part. Thus, within the same family there are highly conserved receptors and peptide ligands as well as one rapidly evolving receptor and ligand.

References (64)

Y. Dumont et al.
Neuropeptide Y and neuropeptide Y receptor subtypes in brain and peripheral tissues
Prog. Neurobiol.
(1992)
L. Grundemar et al.
Neuropeptide Y effector systems: perspectives for drug development
Trends Pharmacol. Sci.
(1994)
D.R. Gehlert
Subtypes of receptors for neuropeptide Y: Implications for the targeting of therapeutics
Life Sci.
(1994)
A. Balasubramaniam et al.
Characterization of neuropeptide Y binding sites in rat cardiac ventricular membranes
Peptides
(1990)
C. Wahlestedt et al.
Identification of cultured cells selectively expressing Y1-, Y2-, or Y3-type receptors for neuropeptide Y/peptide YY
Life Sci.
(1992)
T.W. Schwartz et al.
Receptors on phaeochromocytoma cells for two members of the PP-fold family — NPY and PP
FEBS Lett.
(1987)
K. Nata et al.
Identification of a novel 65-kDa cell surface receptor common to pancreatic polypeptide, neuropeptide Y and peptide YY
Biochem. Biophys. Res. Comm.
(1990)
D. Larhammar et al.
Cloning and functional expression of a human neuropeptide Y/peptide YY receptor of the Y1 type
J. Biol. Chem.
(1992)
C. Eva et al.
Molecular cloning of a novel G protein-couple receptor that may belong to the neuropeptide receptor family
FEBS Lett.
(1990)
M. Nakamura et al.
Identification of two isoforms of mouse neuropeptide Y-Y1 receptor generated by alternative splicing
J. Biol. Chem.
(1995)

J.D. Mikkelsen et al.

A high concentration of NPY (Y1)-receptor mRNA-expressing cells in the hypothalamic arcuate nucleus

Neurosci. Lett.

(1992)

E.E. Jazin et al.

Expression of peptide YY and mRNA for the $NPY PYY$ receptor of the Y1 subtype in dorsal root ganglia during rat embryogenesis

Dev. Brain Res.

(1993)

C. Eva et al.

The murine NPY-1 receptor gene

Structure and delineation of tissue-specific expression

FEBS Lett.

(1992)

H. Herzog et al.

Genomic organization, localization, and allelic differences in the gene for the human neuropeptide Y Y1 receptor

J. Biol. Chem.

(1993)

Y. Dumont et al.

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

Eur. J. Pharmacol.

(1990)

S.P. Sheikh et al.

Y1 and Y2 receptors for neuropeptide Y

FEBS Lett.

(1989)

S.P. Sheikh et al.

Binding of monoiodinated neuropeptide Y to hippocampal membranes and human neuroblastoma cell lines

J. Biol. Chem.

(1989)

C. Gerald et al.

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

J. Biol. Chem.

(1995)

P.M. Rose et al.

Cloning and functional expression of a cDNA encoding a human type 2 neuropeptide Y receptor

J. Biol. Chem.

(1995)

K. Rudolf et al.

The first highly potent and selective non-peptide neuropeptide Y Y1 receptor antagonist: BIBP3226

Eur. J. Pharmacol.

(1994)

J.A. Bard et al.

Cloning and functional expression of a human Y4 subtype receptor for pancreatic polypeptide, neuropeptide Y, and peptide YY

J. Biol. Chem.

(1995)

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)

P. Gregor et al.

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

FEBS Lett.

(1996)

X.-J. Li et al.

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

J. Biol. Chem.

(1992)

E.E. Jazin et al.

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

Regul. Pept.

(1993)

P. Vernier et al.

An evolutionary view of drug-receptor interaction: the bioamine receptor family

Trends Pharmacol. Sci.

(1995)

M. Mukoyama et al.

Expression cloning of type 2 angiotensin II receptor reveals a unique class of seven-transmembrane receptors

J. Biol. Chem.

(1993)

P. Walker et al.

Acidic residues in extracellular loops of the human Y1 neuropeptide Y receptor are essential for ligand binding

J. Biol. Chem.

(1994)

M. Sautel et al.

Role of a hydrophobic pocket of the human Y1 neuropeptide Y receptor in ligand binding

Mol. Cell. Endocrinol.

(1995)

D. Larhammar

Evolution of neuropeptide Y, peptide YY, and pancreatic polypeptide

Regul. Pept.

(1996)

M.M. Rosenkilde et al.

Mutations along transmembrane segment II of the NK-1 receptor affect substance P competition with non-peptide antagonists but not substance P binding

J. Biol. Chem.

(1994)

D. Larhammar et al.

Evolution of neuropeptide Y and its related peptides

Comp. Biochem. Physiol.

(1993)

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ReviewStructural diversity of receptors for neuropeptide Y, peptide YY and pancreatic polypeptide

Abstract

Prog. Neurobiol.

Trends Pharmacol. Sci.

Life Sci.

Peptides

Life Sci.

FEBS Lett.

Biochem. Biophys. Res. Comm.

J. Biol. Chem.

FEBS Lett.

J. Biol. Chem.

Neurosci. Lett.

Dev. Brain Res.

FEBS Lett.

J. Biol. Chem.

Eur. J. Pharmacol.

FEBS Lett.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Eur. J. Pharmacol.

J. Biol. Chem.

J. Biol. Chem.

FEBS Lett.

J. Biol. Chem.

Regul. Pept.

Trends Pharmacol. Sci.

J. Biol. Chem.

J. Biol. Chem.

Mol. Cell. Endocrinol.

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J. Biol. Chem.

Comp. Biochem. Physiol.

Review
Structural diversity of receptors for neuropeptide Y, peptide YY and pancreatic polypeptide