PROGLUCAGON-DERIVED PEPTIDES - POSTTRANSLATIONAL PROCESSINGS AND THEIR BIOLOGICAL CONSEQUENCES

Proglucagon, a 160 aminoacid (AA)-protein synthesized in endocrine pancreas, gastric mucosa, intestinal mucosa and the central nervous system (CNS), contains several domains separated by dibasic pairs. The first 69 AA, glicentin, includes oxyntomodulin (OXM, 37 AA) and glucagon (GLU, 29 AA); the difference between the two is a C-terminal basic octapeptide. Two other domains contain glucagon-like peptides, GLP-I and II which have their own biological pathways. Inside the glucagon-containing domain, two types of processing occur in the producing tissues, one leads to GLU (pancreas and stomach), the other leads to a mixture of the octapeptide-containing peptides, glicentin and OXM (intestine, CNS). The presence of the octapeptide deeply modifies the biological specificity of the peptide: OXM is a hormone which regulates gastric acid secretion, the GLU specificity is directed towards the tissues that regulate metabolism and towards cardio-vascular and renal systems. For both types of peptides (octapeptide-containing and octapeptide-free), a potentiation system exists: the first type induces a local somatostatin release which potentiates the inhibitory effect of the hormone. For the second type, a processing by a thiol-endopeptidase at a dibasic site of the hormone occurring in the target tissue releases a C-terminal fragment (19-29) which modulates the cellular Ca2+ concentration via the plasma membrane Ca2+ ATPase, leading to a potentiation of the effect of the hormone which uses cAMP as the second messenger. In the first type of peptides, the same processing seems to occur, the C-terminal fragment (19-37) being the final hormonal messenger.