title: Calcineurin feedback inhibition of agonist-evoked cAMP formation.
abstract: The effects of immunosuppressant blockers of calcineurin (protein phosphatase 2B) on cAMP formation and hormone release were investigated in mouse pituitary tumor (AtT20) cells. Immunosuppressants enhanced corticotropin-releasing factor- and isoproterenol-evoked cAMP production in proportion with their potency to block calcineurin. Further analysis of cAMP production revealed that intracellular Ca2+ derived through voltage-regulated calcium channels reduces cAMP formation induced by corticotropin releasing-factor or beta 2-adrenergic stimulation and that this effect of Ca2+ is inhibited by blockers of calcineurin. AtT20 cells were found to express at least three species of adenylyl cyclase mRNA-encoding types 1 and 6 as well as a novel isotype, which appeared to be the predominant species. In two cell lines expressing very low or undetectable levels of the novel cyclase mRNA (NCB20 and HEK293 cells respectively), corticotropin-releasing factor-induced cAMP formation was not altered upon blockage of calcineurin activity. These data identify calcineurin as a Ca2+ sensor that mediates the negative feedback effect of intracellular Ca2+ on receptor-stimulated cAMP production. Furthermore, the effect of calcineurin on cAMP synthesis appears to be associated with the expression of a novel adenylyl cyclase isotype, which is highly abundant in AtT20 cells.
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology*; D000262:Adenylyl Cyclases / Q000096:biosynthesis*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D019703:Calcineurin; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D002148:Calmodulin-Binding Proteins / Q000037:antagonists & inhibitors*; D002460:Cell Line; D017124:Conserved Sequence; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D003524:Cyclosporins / Q000494:pharmacology; D017931:DNA Primers; D018076:DNA, Complementary; D005246:Feedback; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007527:Isoenzymes / Q000096:biosynthesis; D007545:Isoproterenol / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D008969:Molecular Sequence Data; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D010903:Pituitary Gland, Anterior; D010911:Pituitary Neoplasms; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D017386:Sequence Homology, Amino Acid; D016559:Tacrolimus / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000318:Adrenergic beta-Agonists; D015220:Calcium Channels; D002148:Calmodulin-Binding Proteins; D003524:Cyclosporins; D017931:DNA Primers; D018076:DNA, Complementary; D007166:Immunosuppressive Agents; D007527:Isoenzymes; D012333:RNA, Messenger; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine; D016559:Tacrolimus