ReviewNeuropeptide Y Family of Hormones: Receptor Subtypes and Antagonists
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.
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