The Secretin Family

The discovery of secretin, discussed in the introduction of this chapter, was concluded with the elucidation of the amino acid sequence of the 27 residues constituting the single chain molecule of the hormone  

A comparison of the sequence of secretin with that of the blood sugar elevating hormone from the pancreas, glucagon [124], reveals extensive homology between the two peptides. Not less than 14 positions are occupied by identical amino acids (in the porcine sequences)  

The first synthesis of glucagon was accomplished by E. Wiinsch (Plate 51) and his associates [125] in Munich in 1967. They followed the well-estabUshed segment condensation approach and secured the pancreatic hormone in crystalline form. 

A few years later Said and Mutt [126] discovered an additional biologically active peptide in extracts from hog gut, the vasoactive intestinal peptide (VIP), that has both secretin like and glucagon like effects and resembles both secretin and glucagon in its sequence. VIP also relaxes smooth muscle preparations from the bronchi and from the stomach but more interestingly it appears to be a neuropeptide it also occurs in certain well-defined areas of the brain in high concentration. The full biological role of VIP remains clouded in mystery and is the subject of many ongoing studies. 

Both PHI and PHM inhibit secretion of acidic juice in the stomach and have a pronounced effect in lowering systemic blood pressure. The sequence of GIP, and PHM have been confirmed by synthesis. 

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Several biologically active peptides were isolated from the venom of the American lizard Gila monster [35]. The remarkable homology of these venom peptides with the intestinal peptides of the secretin family is demonstrated here through the comparison of helospectin and helodermin with the vasoactive intestinal peptide (VIP, p. 168)... 

As illustrated in Fig. 15.4-2, three main families of human GPCRs are known. The rhodopsin-like family A is the largest and the best studied from the structural and functional points of view. The other two main subfamilies are the secretin-like receptor family B, which binds several neuropeptides and other peptide hormones, and the metabotropic glutamate receptor (mGluR)-like family C. A still separate group is constituted by the receptors of the frizzled family, for which the direct coupling to heterotrimeric G-proteins is still a matter of debate [5]. 

K. Tatemoto, V. Mutt, Isolation and characterization of the intestinal porcine PHI (PHI-27), a new member of the glucagon-secretin family. Proc. Natl. Acad. Sci. USA 78 6603-6607 (1981) K. Tatemoto, V. Mutt, Chemical determination of polypeptide hormones. Proc. Natl. Acad. Sci. USA 75, 4115-4119 (1978)... 

PACAP is the newest member of the vasoactive intestinal peptide (VIP)/glucagon/secretin family. It is released from nerves, although their location in the gastrointestinal tract is not known. The PACAP receptor exists as several splice variants, and PACAP stimulates Ca signaling in pancreatic adnar cells, showing that this receptor is coupled to both adenylate cyclase and phospholipase C. PACAP stimulates caldum signals and histamine release from the ECL cell. Several variants of this receptor have been shown to be present by reverse transcriptase-polymerase chain reaction (RT-PCR) of an ECL cell cDNA library. 

Peptides of the secretin/VIP family stimulate somatostatin release, and the consequent suppression of gastrin release may account for at least some of the ability of such peptides to inhibit acid secretion in vivo. PACAP, when injected in vivo, inhibits gastrin-stimulated acid secretion this is probably due to stimulation of the fundic D cell at a VIP receptor. When somatostatin-neutralizing antibody is given along with PACAP, acid secretion ensues due to the effect of PACAP on the ECL cell being revealed. 

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