NEUROPEPTIDE Y, PORCINE

Structure

Mature NPY is a linear peptide consisting of 36 aa in mammals, including humans. Both C- and N-terminal residues are Tyr (Y), which is responsible for its name. C-terminal Tyr is amidated. The aa sequence of NPY is homologous to those of peptide YY (PYY: 70%) and the pancreatic polypeptide (PP: 50%). The amino acid sequences of NPY are conserved in mammals and nonmammalian species. Human NPY: Mr. 4272. Solubility is 1.5mg/mL in water and 1mg/mL in 5% acetic acid.

Gene, mRNA, and precursor

The human NPY gene locus is on chromosome 7 (7p15.3), the rat Npy gene locus is on chromosome 4 (4q24), and the mouse Npy gene locus is on chromosome 6 (6 24.04 cM). The NPY mRNA consists of four exons, and is 551 bp in length. In rats, the preproNPY has 98 aa residues, comprising a 29-aa signal peptide, a 36-aa mature NPY, and a 33-aa C-terminal peptide.

Synthesis and release

A potential AP-1 binding site and several potential AP-2 binding sequences, which are activated by cAMP and phorbol ester, are located upstream from the transcriptional initiation site. NPY in the neuron is released in a Ca2+-dependent manner. NPY levels in the hypothalamus of the brain in particular are regulated by energy status and leptin. NPY in the sympathetic nervous system is coreleased with norepinephrine.

Receptors

Five distinct NPY receptors have been cloned, namely Y1, Y2, Y4, Y5, and y6, as seven transmembranespanning GPCRs. They are associated with a member of the Gi and G0 family,5 and thus ligand binding results in the inhibition of adenylyl cyclase and cAMP production. Among the cloned receptors, the Y1, Y2, Y4, and Y5 receptors represent fully defined subtypes while no functional protein of y6 is expressed in primates due to a truncation in the sixth transmembrane domain. The Y3 receptor has not been identified because the evidence is not sufficient to grant its presence.

Agonists and Antagonists

The subtypes Y1, Y2, and Y5 preferentially bind NPY and peptide YY, whereas subtype Y4 preferentially binds PP. Nonpeptide low molecule weight antagonists that are selective for NPY receptor subunits are synthesized.

Biological functions

In the CNS, NPY induces food intake and decreases energy expenditure. NPY induces potent vasoconstriction. It also acts as a chemical mediator that controls the light-dark cycle entrainment of circadian rhythms. NPY modulates memory processes, depressive state, anxiety, stress, and seizure, and in the sympathetic nerve it stimulates catecholamine secretion.

Clinical implications

Numerous findings suggest that selective antagonists for NPY receptor subtypes could be useful for the treatment of metabolic syndromes and obesity. However, no compound has been successful in clinical trials to date.

Description

Neuropeptide Y is a neuropeptide released by neurons in the CNS and sympathetic nerve system to induce several actions in the brain. In 1982, the isolation and identification of NPY from the porcine brain were reported.