OKADAIC ACID DISRUPTS GOLGI STRUCTURE AND IMPAIRS ENZYME-SYNTHESIS AND SECRETION IN THE RAT PANCREAS

Okadaic acid, a serine/threonine phosphatase inhibitor, has been shown to inhibit rat pancreatic enzyme secretion by interference with late processes in stimulus-secretion coupling. To further characterize its action, we studied the effect of okadaic acid on secretion of newly sy nthesized proteins, protein synthesis, and cellular ultrastructure in pancreatic lobules derived from rats stimulated in vivo by feeding the synthetic proteinase inhibitor FOY-305. Okadaic acid completely block ed protein secretion at concentrations that inhibit the Ca2+/calmoduli n-dependent protein phosphatase 2b, calcineurin. Protein synthesis was abolished at 10(-6) mol/l and reduced by 60% at 5 x 10(-7) mol/l okad aic acid. Pancreatic lobules exposed to 5 x 10(-7) mol/l okadaic acid for 20 min fully restored their secretory capacity on removal of the d rug; whereas, after a preincubation with okadaic acid for >40 min, pro tein secretion remained impaired during the recovery period. Electron microscopic examination of pancreatic acinar cells treated with 5 x 10 (-7) mol/l okadaic acid revealed a dilated Golgi complex after 15 and 30 min and a subsequent fragmentation of Golgi cisternae into clouds o f small uniform vesicles after 60 min. Reassembly of Golgi stacks occu rred after a 60-min recovery without okadaic acid. These data indicate that serine/threonine phosphatases play an important role not only in the regulation of pancreatic enzyme synthesis and exocytosis but also are crucial for the maintenance of normal Golgi architecture and func tion in the exocrine rat pancreas. These effects are probably not excl usively mediated via type 2b calcineurin-like protein phosphatases.