231even higher when the C-terminal fragment is compared. This is not surprising
considering that it is the biological active part of the peptide. Indeed, this fragment
was shown to inhibit the first and second phases of glucose-stimulated insulin
release in a dose dependent way, being residues 35–36 (Glu-Glu) essential for this
activity (Zhang et al. 1990 ).
Molecular Forms
Regarding the existing PST isoforms, a variety of them has been described in human
tumors and blood (Tamamura et al. 1990 , Kitayama et al. 1994 , Funakoshi et al.
1989a) as well as several rat tissues (Hakanson et al. 1995 ; Curry et al. 1990 ). These
forms clearly differ in the length of the peptide chain, but they still share the biologi-
cally active C terminus. Thus, we can find fragments between 29 and 186 aa, being
the PST-52 the most abundant in the human plasma (Kitayama et al. 1994 ).
Finally, diverse kinds of phosphorylated PST forms have been described. This
differences in phosphate residues are correlated with the physical location.
Moreover, there is a correlation between the degree of phosphorylation of the
CGA and it’s processing in different tissues. Thus, CGA and PST are highly
phosphorylated at pancreas, where the most mature form of PST is secreted,
while, in the ilium, phosphorylation is poor and there is no processing of PST
(Watkinson et al. 1993 ).
Pancreastatin Synthesis and Secretion
The cleavage of PST from CGA is specific for each specie and tissue, and occurs
both inside and outside the cell, mainly in the pituitary gland, the endocrine pan-
creas and stomach (Watkinson et al. 1991 ; Simon and Aunis 1989 ; Metz-Boutigue
et al. 1993 ; Leduc et al. 1990 ; Curry et al. 1991 ). It is in the stomach and endocrine
pancreas, were the more complete processing of CGA is carried out, being the PST
peptide its major product. Although many different molecular forms of PST can
arise in the process, all of them share the C-terminus, the biologically active
sequence (Tamamura et al. 1990 ; Schmidt et al. 1988 ; Sekiya et al. 1994 ; Hakanson
et al. 1995 ; Funakoshi et al. 1989b; Curry et al. 1990 ). The best known processing
and secretion system of PST is, certainly, that studied in entherocromaffin cells
(ECL) of the gastric antrum. These cells respond to the gastrin stimulation increas-
ing CGA expression, and consequently, the plasma PST levels. This upward effect
has been achieved in vivo (rodent model), either directly by gastrin infusion or by
suppressing acid secretion, whereas the drop of gastrin levels was due to fasting or
antrectomy, resulting in a decreased plasmatic PST levels. According to this results,
gastrinoma patients present increased plasma PST, which proceed from both, tumor
secretions as well as normal gastrin stimulation (Hakanson et al. 1995 ). It is there-
fore not surprising that higher PST secretion takes place in human insulinoma cells,
compared with primary islets (Hakanson et al. 1992 ).
Action and Mechanisms of Action of the Chromogranin A Derived Peptide Pancreastatin