PANCREATIC POLYPEPTIDE, HUMAN

Discovery

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.

Structure

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. 

Gene and mRNA

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.

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 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

Agonists and antagonists for the Y4 receptor are discussed in Subchapter 34B.

Biological functions

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.

Clinical implications

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.

Description

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 K_i 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 (K_is = 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.

Clinical Use

PP secretion from the pancreas in response to vagal nerve stimulation has been used as a diagnostic test of vagal nerve function.

storage

Store at -20°C