Evidence for redundancy in propeptide/prohormone convertase activities in processing proglucagon: an antisense study

Area of Science:

• Neuroendocrinology
• Molecular Biology
• Biochemistry

Background:

• Prohormone convertases (PCs) are crucial for processing neuroendocrine prohormones.
• Proglucagon is a key precursor for various biologically active peptides, including glucagon.
• Understanding PC roles in proglucagon processing is vital for comprehending peptide hormone regulation.

Purpose of the Study:

• To investigate the specific physiological roles of prohormone convertase 1/3 (PC1/3) and prohormone convertase 2 (PC2) in proglucagon processing.
• To elucidate the contribution of each PC enzyme to the generation of distinct proglucagon-derived peptides.

Main Methods:

• Alpha TC1-6 cells were transfected with antisense or sense vectors for PC1/3 and PC2.
• Radioimmunoassays (RIAs) quantified endogenous PC1/3 and PC2 levels.
• Metabolic labeling with [3H]tryptophan followed by HPLC and peptide mapping analyzed proglucagon and its products.

Main Results:

• Antisense PC1/3 transfection reduced PC1/3 levels by 40% and significantly decreased glicentin production, with partial reduction in other products.
• Antisense PC2 transfection reduced PC2 levels by 91% and significantly decreased glicentin and 9K glucagon, without affecting other peptides.
• PC1/3 influenced the processing of most proglucagon-derived peptides, whereas PC2 predominantly affected specific cleavage sites.

Conclusions:

• PC1/3 plays a major role in processing most proglucagon-derived peptides.
• PC2 activity is more specific, primarily impacting the generation of glicentin and 9K glucagon.
• Redundant mechanisms likely ensure the complete processing of proglucagon, despite the specific roles of PC1/3 and PC2.