Modulation of cyclic AMP action in the dog thyroid by its agonist and antagonist Sp- and Rp-adenosine 3',5'-monophosphorothioate.
The diastereoisomeric forms of adenosine 3',5'-monophosphorothioate, Sp-cAMPS and Rp-cAMPS, have been shown to mimic and to inhibit activation of protein kinase type I and type II by cyclic AMP. In the present work, Sp-cAMPS mimicked thyrotropin (TSH) action on thyroid hormone secretion and protein iodination in dog thyroid slices, whereas Rp-cAMPS antagonized those effects. The phosphorothioates have been tested as inhibitors or activators of the three major phosphodiesterases: the Ca2+/calmodulin-sensitive form, the cyclic GMP-stimulated form and the cyclic AMP-specific enzyme. At 100 microM Sp-cAMPS inhibited the three enzyme activities. In contrast, Rp-cAMPS failed to stimulate activity of the three enzymes. From a comparison of the biological properties of Sp- and Rp-cAMPS and 3-isobutyl-1-methyl xanthine, it is suggested that one site of action of the phosphorothioates is on the cyclic AMP-dependent protein kinases, i.e. the effects of Sp-cAMPS and Rp-cAMPS observed in intact cell can be ascribed to the agonistic and antagonistic effects on the cyclic AMP-dependent protein kinases. However, partial inhibition of phosphodiesterase activities by the phosphorothioates cannot be excluded.
D000818:Animals; D001921:Brain / Q000201:enzymology; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D004285:Dogs; D004789:Enzyme Activation / Q000187:drug effects; D007455:Iodine / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D013237:Stereoisomerism; D013873:Thionucleotides / Q000494:pharmacology*; D013961:Thyroid Gland / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D013972:Thyrotropin / Q000494:pharmacology
D010726:Phosphodiesterase Inhibitors; D011506:Proteins; D013873:Thionucleotides; C016957:adenosine-3',5'-cyclic phosphorothioate; D013972:Thyrotropin; D007455:Iodine; D000242:Cyclic AMP