Pancreastatin inhibits insulin secretion in RINm5F cells through obstruction of G-protein mediated, calcium-directed exocytosis.
To elucidate the regulatory pathway through which pancreastatin inhibits insulin secretion, RINm5F insulinoma cells were challenged with physiological and pharmacological probes known to stimulate insulin release through different mechanisms. Utilizing the electrophysiological technique of capacitance measurements as a correlate to exocytosis, pancreastatin was found to significantly diminish maximum capacitance changes evoked by glyceraldehyde, an effect which was attenuated in pertussis toxin-treated cells. In static incubations of this cell line, pancreastatin significantly inhibited insulin secretion stimulated by glyceraldehyde, carbachol and A23187, secretagogues known to directly elevate beta-cell cytosolic Ca2+. This peptide also inhibited insulin secretion stimulated by phorbol myristate acetate (PMA), but only at incubation times < or = 15 min. It was without effect on insulin secretion stimulated by mastoparan and longer incubations (30 min) with PMA, where the secretory mechanisms are not necessarily Ca(2+)-dependent. Additionally, pancreastatin had no effect on carbachol-generated inositol phosphate accumulation but inhibited simultaneously stimulated insulin secretion. All inhibitory effects of pancreastatin were pertussis toxin sensitive. These results suggest that pancreastatin inhibits insulin secretion in RINm5F cells through a G-protein regulated mechanism at a control point involved in the Ca(2+)-directed exocytotic machinery, a feature shared by other physiologic inhibitors of insulin secretion.
Hertelendy
Z I
ZI
Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, OH 45267-0004, USA.
Patel
D G
DG
Knittel
J J
JJ
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002217:Carbachol / Q000494:pharmacology; D053379:Chromogranin A; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D005985:Glyceraldehyde / Q000494:pharmacology; D007295:Inositol Phosphates / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007340:Insulinoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins; D010187:Pancreatic Hormones / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010455:Peptides; D037342:Pertussis Toxin; D010703:Phorbol Esters / Q000494:pharmacology; D051381:Rats; D014407:Tumor Cells, Cultured; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D014862:Wasp Venoms / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D053379:Chromogranin A; D007295:Inositol Phosphates; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D010187:Pancreatic Hormones; D010455:Peptides; D010703:Phorbol Esters; D010566:Virulence Factors, Bordetella; D014862:Wasp Venoms; C050836:pancreastatin; D005985:Glyceraldehyde; D000001:Calcimycin; C037500:mastoparan; D002217:Carbachol; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D002118:Calcium