Introduction to the reviews on neuropeptide Y
Introduction
This issue of neuropeptides contains 12 invited reviews on the role of neuropeptide Y (NPY) on physiological function. These reviews highlight important topics and exciting new findings that pave the way for future understanding of this peptide. These important references should allow new investigators to obtain a comprehensive understanding the state of this field. NPY was first isolated from pig brain by Tatemoto and Mutt using a method to identify peptides with an amidated carboxy-terminus (Tatemoto et al., 1982; Tatemoto, 1982a). NPY is a member of a peptide family consisting of NPY and two gut hormones, peptide YY (PYY) (Tatemoto, 1982b) and pancreatic polypeptide (PP) (Kimmel et al., 1975). While NPY is strictly localized in neurons and PP is found mainly in endocrine pancreas, PYY is found in both endocrine cells and neurons and, therefore, may exhibit neurotransmitter functions as well.
NPY, PYY, and PP share a common hairpin-like three-dimensional structure that has been called the PP-fold (Fuhlendorff et al., 1990a). The general structure of this peptide family was first established using X-ray crystallography of avian PP (Blundell et al., 1981). In this structural conformation, amino acid residues 1–8 form a type II proline helix followed by a loop. Residues 15–32 form an α-helix, and the four most carboxy-terminal residues are in a flexible loop conformation. As described in the contribution by Larhammar and coworkers, NPY is one of the most evolutionary conserved peptides known. When comparing the amino acid sequences from a variety of mammals, only 2 of the 36 amino acids of NPY are variable. On the other hand, PYY exhibits eight variable amino acids between different orders of mammals and, because PP has evolved very rapidly, it is one of the least conserved peptides known. Despite the limited conservation observed in the PP and PYY amino acid sequences, the general three-dimensional structure is maintained.
The NPY gene is located on human chromosome 7 at the locus 7p15.1 (Cerda-Reverter and Larhammar, 2000). It is composed of four exons and results in the synthesis of a 97 amino acid pre-pro NPY. This is in turn proteolytically processed into the C-terminal peptide of NPY (CPON) and NPY. The C-terminus of NPY is amidated and this is essential for its biological activity. Two enzymes, dipeptidyl peptidase IV and aminopeptidase P can further process NPY–NPY3-36 and NPY2-36, respectively. While the functional significance of CPON is unknown, the C-terminal fragments of NPY have some selectivity for the Y2 receptor subtype (see below). NPY is abundantly expressed in numerous brain regions including the hypothalamus, amygdala, hippocampus, nucleus of the solitary tract, locus coeruleus, nucleus acumbens and cerebral cortex (Chronwall et al., 1985). NPY is also abundantly expressed in the periphery. The adrenal medulla is the primary source of circulating NPY (Cavadas et al., 2002) though it is also expressed in liver, heart, spleen and in endothelial cells of blood vessels (Strand, 1999). NPY is abundant in the sympathetic nervous system where it is co-stored and co-released with norepinephrine (Sundler et al., 1993). It is also expressed in a subpopulation of parasympathetic neurons. Brain NPY is found colocalized with norepinephrine, GABA, somatostatin in agouti-related protein containing neurons (for review see Kask et al., 2002).
Section snippets
Overview of NPY receptors
NPY, PYY, and PP interact with a family of G-protein coupled receptors belonging to the rhodopsin like superfamily (class 1) of receptors. Five NPY receptors have been cloned from mammals (Y1, Y2, Y4, Y5, and y6) and several additional receptors such as the Y3 have been postulated based on pharmacological profiles using various tissue preparations (for review see Berglund et al., 2003a). The y6 receptor has been given the lower case designation (IUPAR nomenclature (Michel et al., 1998) since
NPY receptor subtypes in physiology and disease
While numerous advances have been made in our understanding of NPY, the cloning and pharmacological dissection of the receptors may be the most important recent milestone in the recent history of this field. These receptor sequences have allowed the production of antibodies to elucidate the central distribution of NPY receptor subtypes in the brain (see contribution by Hokfelt et al.). By cloning these receptors from a variety of species, Larhammar and his coworker have provided fascinating
Acknowledgements
I thank my co-editor, Dr. Jacqueline Crawley for her assistance, enthusiasm and patience in putting this issue together. I also thank Dr. Douglas Schober for his helpful comments on the manuscript.
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