Secretin stimulates cyclic AMP and inositol trisphosphate production in rat pancreatic acinar tissue by two fully independent mechanisms.
In rat pancreatic acinar tissue adenylate cyclase is stimulated by low concentrations of secretin, while higher concentrations also activate phosphatidylinositol bisphosphate hydrolysis. By the use of the secretin analogues [Tyr10,13]secretin and [Tyr10,13,Phe22,Trp25]secretin, we have shown that substitution of tyrosine for leucine at positions 10 and 13 was sufficient to reduce the ability of the peptide to stimulate the production of inositol trisphosphate and the increases in cytosolic free calcium, while the ability to stimulate cAMP is little affected and the peptide remained a full agonist. Incubation with cholera toxin caused increases in cAMP, which were maximal after 30 min. Cholera toxin treatment also resulted in a marked reduction of secretin-stimulated inositol trisphosphate production, but this required a much more prolonged treatment (150-240 min), suggesting that different cholera toxin substrates were involved. Activation of protein kinase C with the phorbol ester phorbol 12-myristate 13-acetate had no effect on secretin-induced cAMP formation, nor was secretin-stimulated inositol trisphosphate formation altered by further increases in cAMP. These results indicate that the mechanisms by which secretin stimulates adenylate cyclase and activates phospholipase C in acinar tissue are completely independent.
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D066298:In Vitro Techniques; D015544:Inositol 1,4,5-Trisphosphate; D007295:Inositol Phosphates / Q000096:biosynthesis*; D007700:Kinetics; D008297:Male; D010179:Pancreas / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012633:Secretin / Q000031:analogs & derivatives / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013403:Sugar Phosphates / Q000096:biosynthesis*
D007295:Inositol Phosphates; D013403:Sugar Phosphates; D012633:Secretin; D015544:Inositol 1,4,5-Trisphosphate; D002217:Carbachol; D000242:Cyclic AMP; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine