Neuropeptide Y 、神經(jīng)肽Y

Definition

Neuropeptide Y (NPY) is a 36 amino acid protein which acts as a transmitter in the nervous system1.

Related peptides

NPY has a high degree of sequence homology with peptide YY (70%), a porcine intestinal peptide, and pancreatic polypeptide (50%). It is therefore proposed that NPY, peptide YY, and pancreatic polypeptide are members of the same peptide family1.

Discovery

Originally isolated from porcine brain by Tatemoto et al., in 1982, NPY has been identified throughout the peripheral nervous system and in the adrenal medulla, often in close association with nerve fibres containing noradrenaline1, 2.

Structural Characteristics

The amino acid sequence of NPY, a 36-residue peptide recently isolated from porcine brain, has been determined by using high performance liquid chromatography for separation of its tryptic and chymotryptic fragments and subsequent sequence analysis of the isolated fragments by an improved dansyl Edman subtractive technique. The amino acid sequence of neuropeptide Y has been found to be: Tyr-Pro-Ser-Lys-Pro-Asp-Asn-Pro-Gly-Glu-Asp-Ala-Pro-Ala-Glu-Asp-Leu-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH2. NPY is characterized by N-terminal tyrosine and C-terminal tyrosine amide residues (Tatemoto, 1982) 1. It has been hypothesized that biological activities of NPY are related to its ability to form an a-helix, represented by the fragment NPY (14–31) 3.

NPY Analogs: Porcine neuropeptide Y (pNPY) has been proposed to form an intramolecularly stabilized structure characterized by N- and C-terminal helical regions arranged antiparallel due to a central turn region. Analogs based on this structural model that have the central turn region and various amounts of the helical regions removed, yet retain the N and C termini in a similar spatial orientation are designed. The gap formed by removal of the central residues (residues 8-17 or 7-20) is spanned with a single 8-aminooctanoic acid residue (Aoc) and the structure is further stabilized by the introduction of a disulfide bridge. Synthesized analogs [D-Cys7, Aoc8-17, Cys20] pNPY and [Cys5,Aoc7-20,D-Cys24]pNPY, were found to have receptor binding affinities of 2.3 nM and 150 nM, respectively, in mouse brain membranes (pNPY affinity is 3.6 nM in this assay). It is proposed that the central region (residues 7-17) of pNPY serves a structural role in the peptide and is not involved in direct receptor interaction3.

NPY analog ANA-NPY or [Leu-17, Gln-19, Ala-20, Ala-23, Leu-28, Leu-31] NPY(13–36)-amide binds to postjunctional or Y1 receptors to raise blood pressure and to prejunctional or Y2 receptors to inhibit neurotransmitter release. ANA-NPY affects Y2 receptors in the same way as intact NPY but exhibits far less potent effects on Y1 receptors. ANA-NPY exhibits a helical structure with strong amphipathic character with a bend around Glu-24 indicating that the C-terminal segment 25–35 forms a single a-helical motif4.

NYP Fragments: The mature NPY protein, one of the most abundant neuropeptides in the CNS that possesses an amidated C-terminal residue. The NPY can be cleaved by dipeptidyl peptidase IV and aminopeptidase P resulting in NPY 3–36 and NPY 2–36, respectively, and these fragments are agonists of the Y2/Y5 receptors. Although considerable attention has been devoted to the NPY 2–36 and NPY 3–36 because of their ability to regulate food intake, less is known about the intriguing role of alternative, shorter NPY C-Terminal Fragments (21–36, 31–36)5.

Mode of Action

NPY a 36-mer neuromodulator binds to the receptors Y1, Y2, Y4 and Y5 with nanomolar affinity. They all belong to the rhodopsin-like G-protein coupled seven transmembrane helix spanning receptors. All subtypes belong to the large superfamily of the G-protein-coupled, heptahelical receptors. The different receptor subtypes are localised in various tissues, in the central nervous system as well as in the periphery. Tissues with high density of NPY receptors are blood vessels, kidney, adrenal glands, colon, heart, pancreas, intestine, nerve endings and brain6. Stress exaggerates diet-induced obesity through a peripheral mechanism in the abdominal white adipose tissue that is mediated by NPY. Stressors such as exposure to cold or aggression lead to the release of NPY from sympathetic nerves, which in turn up regulate NPY and its Y2 receptors (NPY2R) in a glucocorticoid-dependent manner in the abdominal fat. This positive feedback response by NPY leads to the growth of abdominal fat. Release of NPY and activation of NPY2R stimulates fat angiogenesis, macrophage infiltration, and the proliferation and differentiation of new adipocytes, resulting in abdominal obesity and a metabolic syndrome-like condition7.

Functions

One of the most striking actions of NPY is the stimulation of food intake in a variety of vertebrate species. But also various other biological effects have been attributed to NPY, e.g., profound effects on secretion of luteinising hormone as well as on growth hormone and insulin release. These observations suggest the important role of NPY in the pathophysiology of obesity and diabetes. Furthermore, it has been reported that NPY elicits potent vasoconstriction, facilitates learning and memory retention processes, modulates locomotor behaviors, produces hypothermia, inhibits sexual behavior, shifts the circadian rhythms, modulates cardio respiratory parameters, generates anxiolytic effects, and inhibits alcohol consumption and resistance6.

References

1.Tatemoto K. (1982). Neuropeptide Y: complete amino acid sequence of the brain peptide. PNAS., 79(18): 5485–5489.

2.Allen JM, Bircham PM, Bloom SR, Edwards AV. (1984). Release of Neuropeptide Y in response to splancnic nerve stimulation in the conscious calf. J. Physio. 357: 401-408.

3.Krstenansky JL, Owen TJ, Buck SH, Hagaman KA, McLean LR. (1989). Centrally truncated and stabilized porcine neuropeptide Y analogs: design, synthesis, and mouse brain receptor binding. PNAS.,  86(12):4377–4381.

4.Barden JA, Cuthbertson RM, Potter EK. (1995). Structure of the presynaptic (Y2) receptor-specific neuropeptide Y analog ANA-NPY. Biochim Biophys Acta ., 1250(1):83-89

5.Rose JB, Crews L, Rockenstein E, Adame A, Mante M, Hersh LB, Gage FH, Spencer B, Potkar R, Marr RA, Masliah E.(2009). Neuropeptide Y Fragments Derived from Neprilysin Processing Are Neuroprotective in a Transgenic Model of Alzheimer's disease.  J Neurosc.,,  29(4):1115-1125

6. Eckard CP, Cabrele C, Wieland HA and Beck-Sickinger AG. (2001). Characterisation of Neuropeptide Y Receptor Subtypes by Synthetic NPY Analogues and by Anti-receptor Antibodies. Molecules., 6(5): 448–467

7.Kuo LE, Kitlinska JB, Tilan JU, Li L, Baker SB, Johnson MD, Lee EW, Burnett MS, Fricke ST, Kvetnansky R, Herzog H, Zukowska Z.(2007). Neuropeptide Y acts directly in the periphery on fat tissue and mediates stress-induced obesity and metabolic syndrome. Nat Med., 13(7):803-811.