The biosynthesis of
insulin and
betagranin, a 20-21 kDa co-secreted
chromogranin A-related
protein, were investigated in isolated
insulinoma cells and islets. The
insulinoma tissue processed
proinsulin to
insulin with kinetics similar to those reported in islet tissue. Unlike islets, however, the
insulinoma released almost one-quarter of the newly synthesized
proinsulin into the medium 10-40 min after its formation.
Betagranin was initially immunoprecipitated as a 100 kDa precursor form, which was indistinguishable from
chromogranin A in size and immunoreactivity and by
peptide mapping. After an initial lag of 10-20 min, the precursor was converted progressively into
betagranin, which appeared to be a stable end product. Formation of
betagranin and
insulin from their respective precursors followed a parallel course and could likewise be inhibited by NH4+,
chloroquine and
monensin, added either before labelling or at any point of time up to 15 min after labelling. As with
proinsulin, approximately one-quarter of the
betagranin precursor was released 10-40 min after synthesis. It is concluded that
betagranin is produced by limited proteolysis from a
chromogranin A precursor in pancreatic beta-cells by a cellular pathway indistinguishable from that of
insulin from
proinsulin.
Chromogranin A is highly conserved in the N-terminal region represented by
betagranin, further suggesting that the
biological activity of
chromogranin A may reside in a derived
peptide rather than in the parent molecule.