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Proglucagon Processing Profile in Canine L Cells Expressing Endogenous Prohormone Convertase 1/3 and Prohormone Convertase 2

Beta Cell Biology, Novo Nordisk A/S (A.B.D., H.K.), Novo Allé, DK-2880 Bagsvaerd, Denmark; the Department Physiology, University of British Columbia (A.M.J.B.), Vancouver, British Columbia, Canada V6T 1Z3; and the Department of Medical Physiology, The Panum Institute, University of Copenhagen (J.J.H.), DK-2200 Copenhagen N, Denmark

Address all correspondence and requests for reprints to: Dr. Hans Kofod, Beta Cell Biology, Novo Nordisk A/S, Novo Allé, 6B3.99, DK-2880 Bagsvaerd, Denmark. E-mail: hko{at}novo.dk

The tissue-specific differential processing of proglucagon (Pg) yields glucagon in pancreatic A cells and glucagon-like peptide-1 (GLP-1), GLP-2, and glicentin in intestinal L cells. It has been suggested that the difference in Pg cleavage in A and L cells is due to the presence of distinct prohormone convertases (PC) in the two cell types, PC1/3 in the L cell and PC2 in the A cell. PC2 has been shown to cleave the N-terminal part of Pg, being essential for glucagon formation and PC1/3 to cleave the C-terminal part of Pg, leading to the formation of GLP-1.

However, some of the cleavage sites in Pg have not proven to be substrates exclusively for either PC2 or PC1/3, and the cleavage profile of Pg in a primary cultured L cell has not yet been correlated with the actual presence of PC2 and PC1/3 in the L cell.

We demonstrate here the presence of PC1/3, PC2, and the PC2 chaperone 7b2, in L cells using light immunohistochemistry on sections from canine ileum and on a canine intestinal cell culture enriched for L cells. Analysis of the cultured L cells, using gel chromatography and RIA, confirms the classical intestinal cleavage profile of Pg, resulting in mainly glicentin, oxyntomodulin, GLP-1-(7–37), and GLP-2. Despite the presence of 7b2 and mature PC2, as demonstrated by Western blot, absolute minimal amounts of glucagon were detected.

These data show that the presence of intracellular PC2 and 7b2 in a primary cell possessing Pg does not have to lead to the formation of glucagon. This formation must then require an additional element to occur, or alternatively, the results could be explained by a canine specific organization of PC2 and Pg into separate compartments, which would prevent interaction.

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