Molecular recognition of the NPY hormone family by their receptors
Introduction
Many neuropeptide systems consist of several closely related peptides that bind to more than one receptor subtype. Such a multireceptor/multiligand system is the Y-receptor family. This family consists of four different Y-receptor subtypes in humans and three native ligands, which belong to the neuropeptide Y (NPY) hormone family. The receptor family and the peptide family are involved in a variety of physiologic functions, including memory retention and control of blood pressure. The most pronounced effect, however, is the regulation of food intake. We focus on the different molecular recognition pattern of the peptides NPY, peptide YY (PYY), and pancreatic polypeptide (PP) by the different Y-receptor subtypes. Several studies have been performed to investigate the interaction between Y receptors and their respective ligands. Up to now the Y1 receptor has been extensively studied, in contrast to the other Y-receptor subtypes. A recently published study reported on the first systematic mutational investigations on the hY2, hY4, and hY5 receptors. We provide an overview on the investigation of this highly important multireceptor/multiligand system.
Section snippets
Ligands
Neuropeptide Y was first isolated in 1982 from porcine brain [1]. It is widely distributed throughout the mammalian brain and is one of the most potent orexigenic factors [2]. PYY, which has a high sequence identity to NPY, also was isolated from porcine intestine in 1982 by Tatemoto [3]. The peptide has tyrosines at both ends and was therefore named “peptide YY.” Produced by the intestinal L-cells, the highest tissue concentrations of PYY are found in distal segments of the gastrointestinal
Y-receptor subtypes
Neuropeptide Y, PYY, and PP bind to a large and very heterogeneous family of G-protein–coupled receptors, which belong to the rhodopsin-like superfamily (class A) of receptors. At least five Y receptors have been cloned from mammals (Y1, Y2, Y4, Y5, and y6). Cloned Y1, Y2, Y4, Y5, and y6 receptors have been shown to couple to inhibitory G-proteins (Gi) and thus mediate inhibition of cyclic adenosine monophosphate synthesis [8]. Currently, four different Y receptor subtypes have been cloned from
Investigation of ligand–receptor interactions
Structure affinity/activity relationship studies can be used to characterize the interaction between ligand and receptor. Essential segments of the peptide and essential segments of the receptor for the interaction can be identified and distinguished from non-essential ones.
Y1 receptor
The Y1 receptor consists of 384 amino acids and was the first member of the NPY receptor family to be cloned. It is mainly expressed in the hypothalamus, in adipose tissue, and in vascular smooth muscle cells. The Y1-receptor subtype has several effects on food intake, anxiolysis, and vasoconstriction and shows high affinity for PYY and NPY, but binds PP with lower affinity. Three glycosylation sites are located on the extracellular side in the amino terminus and one in the second extracellular
Y2 receptor
The Y2 receptor subtype is predominantly expressed as a 381-amino acid protein in the brain and the hippocampus. It has effects on the regulation of the circadian rhythm and memory retention and is involved in angiogenesis. Most effects of the Y2 receptor are mediated by presynaptic suppression of neurotransmitter release. The Y2 receptor exhibits only one consensus site for N-linked glycosylation in the N-terminal part.
Like the Y1-receptor subtype, Y2 shows a high affinity to NPY and PYY, but
Y4 receptor
The Y4 receptor consists of 375 amino acids including four glycosylation sites in the extracellular regions. The receptor protein is predominantly expressed in the gastrointestinal tract, but it is also found in the heart, hypothalamus, and hippocampus. The cDNA of the hY4 receptor was cloned in 1995 by sequence homology screening with the Y1-receptor probe. The receptor protein has higher homology with the hY1 (46%) than with the hY2 (33%) or the hY5 (23%) receptor. Therefore, it is a member
Y5 receptor
The Y5 receptor was first cloned from rat tissue in 1996 [32], [33]. The Y5-receptor gene generates two splice variants. The transcripts differ in an N-terminal 10-amino acid extension. The long isoform consists of 455 amino acids, whereas the short isoform has only 445 amino acids. However, the two receptor isoforms have similar pharmacologic profiles [34]. In contrast to the peripheral expression patterns described for the Y1, Y2, and Y4 receptors, Y5 receptors are rarely observed in
Y6 receptor
The cloning of another Y-receptor subtype has been reported by several groups. This receptor is closely related to the Y1 receptor and therefore another member of the Y1-receptor subfamily. In humans and primates, the sequence contains a deletion of a single nucleotide in the third intracellular loop causing a frame shift and resulting in a termination codon after the sixth TM region. The truncated receptor protein does not bind a peptide of the NPY hormone family. But not in all mammals does
Ligand binding in all Y receptor subtypes
The five mammalian Y receptors can be sorted into three distinct subfamilies based on their degree of amino acid sequence identity. The subfamilies are named after their first members, i.e., Y1, Y2, and Y5. The overall sequence identity of the five Y-receptor subtypes is only 27–31%. The Y1 subfamily includes subtypes Y1, Y4, and y6, and these share approximately 50% overall identity. In contrast, the Y2 and Y5 subfamilies have no known close relatives in mammals. Moreover, the phylogenetic
References (41)
- et al.
NPY and cohorts in regulating appetite, obesity and metabolic syndrome: beneficial effects of gene therapy
Neuropeptides
(2004) - et al.
Distribution of pancreatic polypeptide and peptide YY
Peptides
(2002) - et al.
Isolation and characterization of a new pancreatic polypeptide hormone
J Biol Chem
(1975) - et al.
Receptor subtype-specific docking of Asp6.59 with C-terminal arginine residues in Y receptor ligands
J Biol Chem
(2007) - et al.
Extracellular loop 3 (ECL3) and ECL3-proximal transmembrane domains VI and VII of the mesotocin and vasotocin receptors confer differential ligand selectivity and signaling activity
Gen Comp Endocrinol
(2008) - et al.
The ligand binding site of NPY at the rat Y1 receptor investigated by site-directed mutagenesis and molecular modeling
Mol Cell Endocrinol
(1998) - et al.
The first highly potent and selective non-peptide neuropeptide Y Y1 receptor antagonist: BIBP3226
Eur J Pharmacol
(1994) - et al.
GW1229, a novel neuropeptide Y Y1 receptor antagonist, inhibits the vasoconstrictor effect on neuropeptide Y in the hamster microcirculation
Eur J Pharmacol
(1997) - et al.
Acidic residues in extracellular loops of the human Y1 neuropeptide Y receptor are essential for ligand binding
J Biol Chem
(1994) - et al.
Role of a hydrophobic pocket of the human Y1 neuropeptide Y receptor in ligand binding
Mol Cell Endocrinol
(1995)
Different binding sites for the neuropeptide Y Y1 antagonists 1229U91 and J-104870 on human Y1 receptors
Peptides
BIIE0246: a selective and high affinity neuropeptide Y Y(2) receptor antagonist
Eur J Pharmacol
Reciprocal mutations of neuropeptide Y receptor Y2 in human and chicken identify amino acids important for antagonist binding
FEBS Lett
Identification of a novel hypothalamic neuropeptide Y receptor associated with feeding behavior
J Biol Chem
Neuropeptide Y receptors; antisecretory control of intestinal epithelial function
Auton Neurosci
L-152,804: orally active and selective neuropeptide Y Y5 receptor antagonist
Biochem Biophys Res Commun
Origins of the many NPY-family receptors in mammals
Peptides
Neuropeptide Ycomplete amino acid sequence of the brain peptide
Proc Natl Acad Sci U S A
Isolation and characterization of peptide YY (PYY), a candidate gut hormone that inhibits pancreatic exocrine secretion
Proc Natl Acad Sci U S A
The pancreatic polypeptide (PP-fold) family: gastrointestinal, vascular, and feeding behavioral implications
Proc Soc Exp Biol Med
Cited by (0)
D. Lindner and J. Stichel contributed equally to the manuscript.
The financial contribution of the DFG for SFB 610, TP A1 is kindly acknowledged.