Influence of the protein kinase C inhibitor 3-[1-[3-(amidinothio) propyl]-1H-indoyl-3-yl]-3-(1-methyl-1H-indoyl-3-yl) maleimide methane sulfonate (Ro-318220) on surfactant secretion in type II pneumocytes.
We have investigated the influence of 3-[1-[3-(amidinothio)propyl]-1H-indoyl-3-yl]-3-(1-methyl-1H- indoyl-3-yl) maleimide methane sulfonate (Ro-318220), a potent and selective inhibitor of protein kinase C, on phosphatidylcholine secretion in response to surfactant secretagogues in rat type II cells. Freshly isolated cells were cultured overnight with [3H]choline to label the phosphatidylcholine pool and were preincubated for 30 min in fresh medium with or without Ro-318220. Secretagogues were then added, and the incubation was continued for 90 min after which [3H]phosphatidylcholine secretion was measured. Ro-318220 (10 microM) almost completely abolished the stimulatory effects of 36 microM terbutaline, 10 microM ATP, and 1 microM 12-O-tetradecanoylphorbol-13-acetate (TPA) and significantly antagonized the effects of 10 microM 5'-(N-ethylcarboxyamido) adenosine (NECA), 100 microM dioctanoylglycerol, and 0.05 microM ionomycin. The effect of Ro-318220 was dependent on concentration. The IC50 values for Ro-318220 inhibition of the effects of terbutaline, NECA, TPA, and ionomycin were not significantly different. The IC50 value for Ro-318220 inhibition of the effect of TPA in the type II cell (0.05 microM) was similar to that reported for inhibition of protein kinase C in vitro (0.08 microM). We conclude that Ro-318220 antagonizes the effects of the different surfactant secretagogues by antagonizing a step common to the different signaling pathways. It remains to be established if it is protein kinase C or another step that is inhibited.
Rooney
S A
SA
Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06510, USA. Seamus.Rooney@Yale.edu
Gobran
L I
LI
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D019830:Adenosine-5'-(N-ethylcarboxamide); D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010713:Phosphatidylcholines / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D011663:Pulmonary Surfactants / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007211:Indoles; D010713:Phosphatidylcholines; D011663:Pulmonary Surfactants; D019830:Adenosine-5'-(N-ethylcarboxamide); D000255:Adenosine Triphosphate; D011493:Protein Kinase C; D000241:Adenosine; D013755:Tetradecanoylphorbol Acetate; C064758:Ro 31-8220