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.
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.
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.
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.
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.
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.
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.
