Neuropeptide Y receptors

The hormone pancreatic polypeptide (PP) is a 36 amino acid peptide, which is closely related to neuropeptide Y and peptide YY PP is mainly found in pancreatic cells distinct from those storing insulin, glucagon or somatostatin. It acts on receptors that belong to the family of neuropeptide Y receptors, particularly on the Y4 subtype. 

De Bono, M. and Bargmann, C.I. (1998) Natural variation in a neuropeptide Y receptor homolog modifies social behaviour and food response in C. elegans. Cell94, 679-689. 

Dinger, M. C Bader, J. E., Kobor, A. D Kretzschmar, A. K., and Beck-Sickinger, A. G. (2003) Homodimerization of neuropeptide Y receptors investigated by fluorescence resonance energy transfer in living cells. J. Biol. Chem. 10,10. 

Broqua P, Wettstein JG, Rocher MN, Gauthiermartin B, Junien JL (1995) Behavioral effects of neuropeptide Y receptor agonists in the elevated plus-maze and fear-potentiated startle procedures. Behav Pharmacol 6 215-222... 

Sajdyk TJ, Schober DA, Gehlert DR (2002a) Neuropeptide Y receptor subtypes in the basolat-eral nucleus of the amygdala modulate anxiogenic responses in rats. Neuropharmacology 43 1165-1172... 

Compounds bearing imidazotriazole subunits have been investigated as neuropeptide Y receptor antagonists for the treatment of hyperphagia, obesity, and diabetes <2004W0050652>. 

Neuropeptide Y and its presynaptic receptors were discovered 25 years ago (Figure 1). There are four subtypes of neuropeptideY receptors, Yi, Y2, Y4 and Y5 (Table 1, Alexander et al. 2006) a fifth subtype, Y6, is functional in the mouse, whereas in primates the related gene is nonfunctional due to a frame-shift mutation (Alexander et al. 2006). Neuropeptide Y receptors are also activated by another two peptides, peptide YY (PYY) and pancreatic polypeptide (PP). The three peptides are not synthetized as such but are processed from larger precursors via two steps, i.e., an initial cleavage of the N-terminal signal peptide and the subsequent cleavage of the C-terminal part (Tatemoto 2004). The affinity of PYY is very similar to that... 

Figure 4 shows how a presynaptic neuropeptide Y receptor was identified in a superfusion model. In mouse brain cortex slices, serotonin release was concentration-dependently inhibited by neuropeptide Y and this effect was potently mimicked by neuropeptide Y-(13-36). Since the latter is selective for Y2 over Yi andYs receptors (Alexander et al. 2006) one may conclude that neuropeptide Y acts via Y2 receptors. 

Many examples of inhibitory presynaptic neuropeptide Y receptors have been found in tissues from experimental animals and humans (Table 3), based on experiments with each of the four techniques described in the Introduction (overflow experiments, electrophysiological techniques, pithed animals, electrically induced twitches in isolated tissues). For the identification of the receptors, the three peptides and modified (e.g., truncated) congeners (Figure 4) were the only tools for many years. More recently, selective antagonists (e.g., in the study by Schwertfeger et al. [2004] on the human heart) and knockout mice (e.g., in the study by Smith-White et al. [2002] on the mouse heart) have been used. According to most studies, only Y2 receptors serve as presynaptic neuropeptide Y receptors. 

Presynaptic neuropeptide Y receptors have been identified in the sympathetic, parasympathetic and enteric nervous system, on sensory neurones, and on many sites in the CNS they inhibit the release of 11 different transmitters (Table 3). Most presynaptic neuropeptide Y receptors are heteroreceptors, but some serve as autoreceptors, both in the sympathetic nervous system (pig spleen and kidney) and the brain (rat hypothalamus) (Table 3). Marked species differences occur. For example, Y2 receptors inhibit the sympathetically mediated tachycardia, the vagally mediated bradycardia, and the vagally mediated bronchoconstriction in the guinea pig but not in the rabbit (Serone et al. 1999 Abrahamsson 2000). Moreover, Y2 receptors inhibit noradrenaline release in the guinea pig carotid but not femoral artery, and conversely inhibit noradrenaline release in the rat femoral but not carotid artery (Potter and Tripovic 2006). 

Y receptors can couple to voltage-dependent K+ channels (step 3 in Figure 3). This may hold true for the neuropeptide Y receptor involved in inhibition of ATP release in the mouse vas deferens (Stjame et al. 1989). For three presynaptic neuropeptide... 

There is now good evidence for a role of presynaptic neuropeptide Y receptors in disease states. As to the cardiovascular system, plasma neuropeptide Y levels are slightly increased in hypertensive patients and to a greater extent in cardiac failure (Morris 2004). An increase in neuropeptide Y levels is even an important prognostic marker for cardiovascular death in hemodialysis patients (Odar-Cederlof et al. 

The exact role played by the presynaptic neuropeptide Y receptor, however, cannot easily be pinpointed for at least two reasons. First, presynaptic inhibitory Y2 receptors occur both on sympathetic and parasympathetic nerve endings of the human heart (Table 3) i.e., they inhibit two opposing systems. Second, within the sympathetic nervous system postsynaptic neuropeptide Y receptors (Yi) lead to vasoconstriction and increase the effect elicited by other vasoconstrictors (Morris... 

Clinical trials with neuropeptide Y receptor ligands have so far not been successful (Brain and Cox 2006). 

Corticotrophin releasing factor ligands - alpha helical CRF has been shown to block the anxiogenic effects of alcohol withdrawal in rats. It is possible that CRF interacts with neuropeptide Y receptors NPY 1 receptor agonists to have anticonflict effects in animal studies. 

Silva, A. P. et al. (2003). Activation of neuropeptide Y receptors is neuropro-tective against excitotoxicity in organotypic hippocampal slice cultures. FASEB J. 17(9), 1118-1120. 

For any medicinal chemist or pharmacologist, the similarity of this compound with the antibiotic tetracycline is striking. However, none of them would a priori forecast that BMS-192548 exhibits CNS activities. Actually, the compound turns out to be a ligand for the neuropeptide Y receptor preparations [48]. 

Huang S. BMS-192548, a tetracyclic binding inhibitor of neuropeptide Y receptors, from Aspergillus niger WB2346. II. Physico-chemical properties and structural characterization. 

Neuropeptide Y receptor. The receptors for neuropeptide Y are G protein-coupled... 

Anchinopeptolides A-D Anchinoe tenacior Ligands of somatostatin, bradykinin and neuropeptide Y receptors... 

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