Phosphatidylinositol hydrolysis and phosphatidylinositol 4',5-diphosphate hydrolysis are separable responses during secretagogue action in the rat pancreas.
Rat pancreatic fragments and acinar preparations were incubated in vitro to characterize further the changes in phosphoinositide metabolism that occur during secretagogue action. Two distinct responses were discernible. The first response, most notably involving a decrease in phosphatidylinositol content, was (a) observed at lower carbachol concentrations in dose-response studies, (b) inhibited by incubation in Ca2+-free media containing 1 mM EGTA, (c) associated with increases in inositol monophosphate production, and (d) provoked by all tissue secretagogues (carbachol, cholecystokinin, secretin, insulin, dibutyryl cAMP and the ionophore A23187), regardless of whether their mechanism of action primarily involved Ca2+ mobilization or cAMP generation. This decrease in phosphatidylinositol content was at least partly due to phospholipase C (and/or D) activation, as evidenced by the increase in inositol monophosphate. The second response, most notably involving markedly increased incorporation of 32PO4 into phosphatidic acid and phosphatidylinositol, was (a) observed at higher carbachol concentrations, (b) not influenced by incubation in Ca2+-free media containing 1 mM EGTA, and (c) associated with increases in inositol triphosphate production. This 32PO4 turnover response was probably largely the result of phospholipase C-mediated hydrolysis of phosphatidylinositol 4',5'-diphosphate, which, as shown previously, also occurs at higher carbachol concentrations and is insensitive to comparable EGTA-induced Ca2+ deficiency. This phosphatidylinositol 4',5'-diphosphate hydrolysis response was only observed in the action of agents (carbachol and cholecystokinin) which mobilize Ca2+ via activation of cell surface receptors. The present results indicate that phosphatidylinositol and phosphatidylinositol 4',5'-diphosphate hydrolysis are truly separable responses to secretagogues acting in the rat pancreas. Furthermore, phosphatidylinositol 4',5'-diphosphate, rather than phosphatidylinositol hydrolysis is more likely to be associated with receptor activation and Ca2+ mobilization.
Farese
R V
RV
Orchard
J L
JL
Larson
R E
RE
Sabir
M A
MA
Davis
J S
JS
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000502:physiology; D002217:Carbachol / Q000494:pharmacology; D002766:Cholecystokinin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D004533:Egtazic Acid / Q000494:pharmacology; D006868:Hydrolysis; D007328:Insulin / Q000494:pharmacology; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism*; D010712:Phosphatidic Acids / Q000378:metabolism; D019269:Phosphatidylinositol 4,5-Diphosphate; D010716:Phosphatidylinositols / Q000378:metabolism*; D010741:Phospholipases A / Q000378:metabolism; D051381:Rats; D012633:Secretin / Q000494:pharmacology; D010738:Type C Phospholipases / Q000378:metabolism
D007328:Insulin; D010712:Phosphatidic Acids; D019269:Phosphatidylinositol 4,5-Diphosphate; D010716:Phosphatidylinositols; D012633:Secretin; D000001:Calcimycin; D004533:Egtazic Acid; D003994:Bucladesine; D002217:Carbachol; D002766:Cholecystokinin; D000242:Cyclic AMP; D010741:Phospholipases A; D010738:Type C Phospholipases; D002118:Calcium