The pancreatic polypeptide (PP) is a peptide hormone
secreted from the pancreas to inhibit pancreatic exocrine
secretion, gall bladder contraction, gastric emptying, and
gut motility, and to modulate anxiolytic and depressive
behaviors. PP was isolated in 1975 as a byproduct of insulin purification from the pancreas.
Mature PP is a linear peptide consisting of 36 aa residues in mammals, including humans. PP is a member
of the neuropeptide Y (NPY) family, and about 50%
homology with NPY and 70% homology with peptide
YY (PYY) in pigs. The amino acid sequences of PP are conserved in mammals and other nonmammalian specie. Human PP: Mr. 4182. Soluble in water, acid solutions,
and methanol.
The human PP gene is localized with the NPY gene on
chromosome 17p21.31 and consists of four exons. In
humans, preproPP has 95 aa residues, comprising a
29-aa signal peptide, a 36-aa mature PP, and a 30-aa
C-terminal peptide. PP gene expression is restricted to the pancreas in the
fourth cell type, named F cells. The PP-producing F cells
often take up a peripheral position in the islets, and are
distinct from the three other major islet cell populations,
the insulin-producing β cells, the glucagon-producing α
cells, and the somatostatin-producing S cells.
A potential AP-1 binding site and several potential
AP-2 binding sequences, which are activated by cAMP
and phorbol ester, are located upstream of the transcriptional initiation site of the human PP gene. PP is secreted
from the F cells of the pancreatic islets. The secretion of
PP is increased by protein meal ingestion, fasting, and
exercise.
Agonists and antagonists for the Y4 receptor are discussed in Subchapter 34B.
PP secreted from the pancreas stimulates gastric juice
secretion. The peripheral administration of PP decreases
food intake in rodents while central administration of
PP increases food intake. PP inhibits pancreatic exocrine
secretion, gall bladder contraction, gastric emptying, and gutmotility.The peripheral administration of PP causes
Y4 receptor-dependent c-Fos expression in the brainstem,
hypothalamus, and amygdala. The chronic peripheral
administration of PP reduces anxiety.
Plasma PP levels are reduced following increased food
intake, and elevated in anorexia nervosa. PP administration reduces food intake in lean humans as well as in
obese patients with Prader-Willi syndrome. No
PP-related peptides and compounds have been used clinically as therapeutic agents.
Pancreatic polypeptide is an agonist of neuropeptide Y (NPY) receptors that reduces forskolin-induced cAMP accumulation in L-M(TK-) cells recombinantly expressing human and rat Y4 receptors (EC50s = 87.1 and 36.3 pM, respectively). It binds to Y1 and Y5 receptors with Ki values of 19 and 3.9 nM, respectively, for human and 50 and 2.4 nM, respectively, for rhesus monkey receptors. Pancreatic polypeptide also binds to rabbit Y1, Y2, Y4, and Y5 receptors (Kis = 0.39, 0.087, 0.79, and 0.24 nM, respectively). It induces contractile responses in isolated rat colon with EC50 values of 1.6 and 0.7 nM for ascending and descending colon segments, respectively. In vivo, pancreatic polypeptide (0.7-7 nmol, i.c.v.) increases food intake in rats.
PP secretion from the pancreas in response to vagal
nerve stimulation has been used as a diagnostic test of
vagal nerve function.
