Pancreatic, Pancreastatin and Chromogranin A Polypeptides

Definition
Pancreatic polypeptide (PP) is a hormone produced by endocrine cells of the duodenal pancreas.
Pancreastatin (PST) is a regulatory peptide with a general inhibitory effect on secretion, is derived from chromogranin A, a glycoprotein present throughout the neuroendocrine system. Chromogranin A (CgA) is also referred to as secretory protein I, is an acidic protein expressed by many neuroendocrine cells and neurons.

Structural Characteristics
PP contains 36 amino acids, has a molecular weight of 4.2 kDa and the isoelectric point is pH 6 to 7. The amino acid sequence of the peptide 1 is Gly-Pro-Ser-Gln-Pro-Thr-Tyr-Pro-Gly-Asp-Asp-Ala-Pro-Val-Glu-Asp-Leu-Ile-Arg-Phe-Tyr-Asp-Asn-Leu-Gln-Gln-Tyr-Leu-Asn-Val-Val-Thr-Arg-His-Arg-Tyr-NH2. The human CgA is a 439-residue protein preceded by an 18-residue signal peptide. Comparison of the protein sequence of human CgA with that of bovine CgA shows high conservation of the NH2-terminal and COOH terminal domains as well as the potential dibasic cleavage sites, whereas the middle portion shows remarkable sequence variation (36%). The PST sequence contained in human CgA is flanked by sites for proteolytic processing. This suggests that human CgA may be the precursor for a human Pancreastatin molecule and possibly for other, as yet unidentified, biologically active peptides 2.

Mode of Action
PP is secreted from and controls differentiation through its specific receptors: In a study, the regulatory roles of PP and its Y receptors were studied using MC3T3-E1 cells, a murine transformed osteoblastic cell line. It was found that PP mRNA was detected and increased during cell-contact-induced differentiation in MC3T3-E1 cells. Furthermore, all the types of NPY family receptor mRNAs (Y1, Y2, Y4, Y5, and y6) were found to increase during differentiation. Also it was found that PP stimulated differentiation in MC3T3-E1 cells in terms of alkaline phosphatase (ALP) mRNA and bone morphogenetic protein-2 (BMP-2) mRNA. These findings suggested that MC3T3-E1 cells produce and secrete PP, which may in turn stimulate the differentiation of MC3T3-E1 through its specific receptors in an autocrine manner 3. PST, a CgA-derived peptide, has been found to modulate glucose, lipid, and protein metabolism in rat adipocytes. PST has an overall counter regulatory effect on insulin action by activating a specific receptor–effector system (Gaq/11protein-PLC-ß-PKC classical). However, PST stimulates both basal and insulin-mediated protein synthesis in rat adipocytes. PST dose-dependently stimulates Thr421/Ser424 phosphorylation of S6 kinase. Moreover, PST promotes phosphorylation of regulatory sites in 4E-BP1 (PHAS-I) (Thr37, Thr46). The initiation factor eIF4E itself, whose activity is also increased upon phosphorylation, is phosphorylated in Ser209 by PST stimulation. Also, it has been shown that that these effects of PST on S6 kinase and the translation machinery can be blocked by preventing the activation of PKC. These results indicate that PST stimulates protein synthesis machinery by activating PKC and provides some evidence of the molecular mechanisms involved, i.e., the activation of S6K and the phosphorylation of 4E-BP1 (PHAS-I) and the initiation factor eIF4E 4.

Functions
Mouse pancreatic polypeptide modulates food intake: A study was conducted to investigate the effects of synthetic mouse pancreatic polypeptide (mPP) on feeding and anxiety in mice. It was found that the intracerebroventricular (i.c.v.) injection of mPP (0.003-3 nmol) dose-dependently increased food intake. A significant increase was observed 20 min after i.c.v. injection and continued for 4 h. Further the intraperitoneal (i.p.) injection of mPP (0.03-30 nmol) dose-dependently decreased food intake. A significant decrease was observed 20 min after i.p. injection and continued for 4 h. In the elevated plus maze test, the i.c.v. injection of mPP (0.003-3 nmol) did not affect anxiety behavior. These results suggest that mPP modulates food intake and the Y4 receptor in the brain may contribute to the regulation of feeding, whereas appearing not to influence anxiety in mice 5.

Effects of PST and CgA on insulin release stimulated by various insulinotropic agents: The effects of porcine PST on insulin release stimulated by insulinotropic agents, glucagon, cholecystokinin-octapeptide (CCK-8), gastric inhibitory polypeptide (GIP) and L-arginine, were compared to those of bovine chromogranin A (CGA) using the isolated perfused rat pancreas. PST significantly potentiated glucagon-stimulated insulin release (first phase: 12.5 ± 0.9 ng/8 min; second phase: 34.5 ± 1.6 ng/25 min in controls; 16.5 ± 1.1 ng/8 min and 44.0 ± 2.2 ng/25 min in pancreastatin group), whereas CgA was ineffective. Similarly, CGA did not affect insulin release stimulated by CCK-8 or GIP. These findings suggest that PST stimulates insulin release in the presence of glucagon. Because PST can have multiple effects on insulin release, which are dependent upon the local concentration of insulin effectors, PST may participate in the fine tuning of insulin release from B cells 6.

References
1. Kimmel JR, Hayden LJ, Pollock HG (1975). Isolation and characterization of a new pancreatic polypeptide hormone. J. Biol. Chem., 250(24):9369-9376.
2. Konecki DS, Benedum UM, Gerdes HH, Huttner WB (1987). The Primary Structure of Human Chromogranin A and Pancreastatin. J. Biol. Chem., 262(35):17026-17030.
3. Hosaka H, Nagata A, Yoshida T, Shibata T, Nagao T, Tanaka T, Saito Y, Tatsuno I (2008). Pancreatic polypeptide is secreted from and controls differentiation through its specific receptors in osteoblastic MC3T3-E1 cells. Peptides, 29(8):1390-1395.
4. González-Yanes C, Sánchez-Margalet V (2002). Pancreastatin, a chromogranin A-derived peptide, activates protein synthesis signaling cascade in rat adipocytes. Biochemical and Biophysical Research Communications, 299(4):525-531.
5. Asakawa A (1999). Mouse pancreatic polypeptide modulates food intake, while not influencing anxiety in mice. Peptides, 20(12):1445-1448.
6. Ishizuka J, Tatemoto K, Cohn DV, Thompson JC, Greeley GH Jr (1991). Effects of pancreastatin and chromogranin A on insulin release stimulated by various insulinotropic agents. Regulatory Peptides, 34(1):25-32.