Both amidated and nonamidated forms of glucagon-like peptide I are synthesized in the rat intestine and the pancreas.
Biologically active peptides are initially synthesized in the form of protein precursors, and the peptides are liberated by post-translational processing from the precursors in a tissue-specific manner. Mammalian proglucagon, which is synthesized in the neuroendocrine L-cells of the intestine and the alpha-cells of the pancreas, contains within its structure the sequences of glucagon and two glucagon-like peptides (GLP-I and GLP-II) flanked at their amino and carboxyl termini by dibasic residues. Tissue-specific processing liberates different peptides in the intestine compared with the pancreas. One of these intestinal peptides, glucagon-like peptide I(7-37) (GLP-I(7-37], is one of the most potent insulin secretagogues studied to date. It contains within its carboxyl-terminal domain an arginine residue that, because of an adjacent glycine residue, may alternatively be used during post-translational processing as a site for amidation. Using a chromatographic system and radioimmunoassays that discriminate among the closely related GLP-I peptides, we find that the processing of proglucagon in the rat intestine and to a lesser extent in the rat pancreas results in the formation of at least three GLP-I peptides, of 37, 31, and 30 residues. The 30-residue peptide is in the form of an alpha-carboxyl-terminal arginine amide, a modification that is not usually found in proteins. Remarkably, the relative potencies for the stimulation of insulin secretion from the perfused rat pancreas of the nonamidated (GLP-I(7-37] and the amidated (GLP-I(7-36) amide) peptides are the same (Weir, G. C., Mojsov, S., Hendrik, G. K., and Habener, J. F. (1989) Diabetes 38, 338-342; Suzuki, S., Kawai, K., Okashir, S., Mukal, H., and Yamashita, K. (1989) Endocrinology 125, 3109-3114).
Mojsov
S
S
Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston 02114.
Kopczynski
M G
MG
Habener
J F
JF
D000818:Animals; D000918:Antibody Specificity; D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D000939:Epitopes / Q000276:immunology; D005934:Glucagon / Q000096:biosynthesis* / Q000276:immunology / Q000302:isolation & purification; D052216:Glucagon-Like Peptide 1; D007106:Immune Sera / Q000276:immunology; D007413:Intestinal Mucosa / Q000378:metabolism*; D010179:Pancreas / Q000378:metabolism*; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000276:immunology / Q000302:isolation & purification; D011498:Protein Precursors / Q000096:biosynthesis* / Q000276:immunology / Q000302:isolation & purification; D011499:Protein Processing, Post-Translational; D011863:Radioimmunoassay; D051381:Rats
D000939:Epitopes; D007106:Immune Sera; D010446:Peptide Fragments; D011498:Protein Precursors; D052216:Glucagon-Like Peptide 1; D005934:Glucagon