Phosphatase inhibitors potentiate adrenergic-stimulated cAMP and cGMP production in rat pinealocytes.
The role of phosphoprotein phosphatase in the regulation of adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP) accumulation in rat pinealocytes was investigated using the three phosphatase inhibitors calyculin A, tautomycin, and okadaic acid. Calyculin A (0.1 microM) was found to enhance the isoproterenol- and norepinephrine-stimulated cAMP accumulation six- and threefold, respectively, whereas tautomycin and okadaic acid were less effective. The effect of calyculin A was rapid (within 5 min) and persisted in the presence of phosphodiesterase inhibition. However, in contrast to protein kinase C activation or intracellular calcium elevation, the phosphatase inhibitors were less effective in potentiating the cAMP response stimulated by forskolin or cholera toxin, and their effects were not blocked by calphostin C or N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide. The adrenergic-stimulated cGMP response was also less sensitive to the phosphatase inhibition. Therefore, our results suggest that 1) the adrenergic-stimulated cAMP signal is subjected to the tonic inhibition by phosphoprotein phosphatase; 2) phosphatase inhibitors enhance cAMP synthesis through their actions at the receptor level; and 3) the cAMP signal is more sensitive to the regulation by phosphorylation than cGMP in rat pinealocytes.
Ho
A K
AK
Department of Physiology, Faculty of Medicine, University of Alberta, Edmonton, Canada.
Chik
C L
CL
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis*; D006152:Cyclic GMP / Q000096:biosynthesis*; D004357:Drug Synergism; D004988:Ethers, Cyclic / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008387:Marine Toxins; D009638:Norepinephrine / Q000494:pharmacology*; D019319:Okadaic Acid; D010080:Oxazoles / Q000494:pharmacology*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D010870:Pineal Gland / Q000187:drug effects / Q000378:metabolism*; D054648:Protein Phosphatase 2; D011714:Pyrans; D051381:Rats; D017207:Rats, Sprague-Dawley; D013141:Spiro Compounds
D000935:Antifungal Agents; D004988:Ethers, Cyclic; D008387:Marine Toxins; D010080:Oxazoles; D011714:Pyrans; D013141:Spiro Compounds; C053079:tautomycin; D019319:Okadaic Acid; C059041:calyculin A; D000242:Cyclic AMP; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D006152:Cyclic GMP; D007545:Isoproterenol; D015056:1-Methyl-3-isobutylxanthine; D009638:Norepinephrine