Elsevier

Nutrition

Volume 24, Issue 9, September 2008, Pages 907-917
Nutrition

Molecular recognition of the NPY hormone family by their receptors

https://doi.org/10.1016/j.nut.2008.06.025Get rights and content

Abstract

Many G-protein–coupled receptors belong to families of different receptor subtypes, which are recognized by a variety of distinct ligands. We summarize the current state of the art of the multireceptor/multiligand system of the so-called Y-receptor family. This family consists of four G-protein–coupled Y receptors in humans (hY1, hY2, hY4, and hY5) and is activated by the so-called neuropeptide Y hormone family, which consists of three native peptide ligands named neuropeptide Y, pancreatic polypeptide, and peptide YY. We recently reported that one conserved aspartate residue in the third extracellular loop is essential for ligand binding in all four Y receptors, but binds the endogenous ligands in a different mode by interacting with different ligand arginine residues. By combining peptide synthesis to obtain chemically modified neuropeptide Y, peptide YY, and pancreatic polypeptide analogs, receptor mutagenesis, and receptor chimeras, we could trace binding and signaling to a molecular level. The data on the variation of the ligands and an overview of the currently known mutagenesis data are summarized and specific models for the binding mode of the three ligands in all four receptors are provided.

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

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    D. Lindner and J. Stichel contributed equally to the manuscript.

    The financial contribution of the DFG for SFB 610, TP A1 is kindly acknowledged.

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