The bifunctional rat pancreatic secretory trypsin inhibitor/monitor peptide provides protection against premature activation of pancreatic juice.
BACKGROUND
In the rat, two forms of the pancreatic secretory trypsin inhibitor, PSTI-I and PSTI-II, are secreted into pancreatic juice. It is assumed that their role is to protect the pancreas from premature activation of the protease-rich pancreatic juice. In the small intestine, PSTI-I, also called 'monitor peptide', is thought to have a different role: PSTI-I competes with protein for activated trypsin. In the presence of a protein-rich meal, free PSTI induces a release of cholecystokinine from the intestine.


METHODS
To investigate whether its role as monitor peptide is compatible with the inhibitory, protective function in the pancreas, PSTI-I was chemically synthesized and then renatured.


RESULTS
The peptide was almost completely trypsin resistant and exhibited a dose-dependent inhibitory activity to bovine and partially purified rat trypsin. Furthermore, experiments with trypsin- and endopeptidase-activated pancreatic juice demonstrated that its inhibitory capacity was sufficient to prevent premature activation. Binding studies of (125)I-labeled PSTI-I with the putative intestinal receptor using isolated membranes indicated the presence of high-affinity binding sites (k(d) = 5 x 10(-8)M). Binding of PSTI-I could be competed with excess PSTI-I or trypsin. In a biological assay system, injections of PSTI-I displayed monitor peptide activity by inducing a dose-dependent trypsinogen release from the pancreas.


CONCLUSIONS
Our experiments support a dual function of PSTI-I: monitoring protein in the gut due to its 'moderate' affinity for trypsin and a protective role in the pancreas.
Graf
R
R
Pancreatitis Research Laboratory, Department of Surgery, University Hospital, Zürich, Switzerland. rgf@chi.usz.ch
Klauser
S
S
Fukuoka
S-I
SI
Schiesser
M
M
Bimmler
D
D
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D010450:Endopeptidases / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D010179:Pancreas / Q000378:metabolism*; D010189:Pancreatic Juice / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000378:metabolism; D014357:Trypsin / Q000494:pharmacology; D014359:Trypsin Inhibitor, Kazal Pancreatic; D014361:Trypsin Inhibitors / Q000494:pharmacology; D014362:Trypsinogen / Q000187:drug effects / Q000378:metabolism
D036341:Intercellular Signaling Peptides and Proteins; D011956:Receptors, Cell Surface; C504705:Spink1 protein, rat; D014361:Trypsin Inhibitors; D014359:Trypsin Inhibitor, Kazal Pancreatic; D014362:Trypsinogen; D010450:Endopeptidases; D014357:Trypsin