Glucocorticoids block protein kinase A inhibition of calcium-activated potassium channels.
Adrenal corticosteroids have well known and profound effects on neurons and neuroendocrine cells, but the underlying cellular mechanisms are poorly understood. The present study analyzed membrane currents and ACTH release in AtT20 mouse pituitary corticotrope tumor cells. Patch-clamp analysis revealed a significant and selective inhibition of calcium-activated (BK-type) potassium channels upon activation of protein kinase A by corticotropin-releasing factor or 8-chlorophenylthio-cAMP. The synthetic glucocorticoid dexamethasone had no effect on potassium currents evoked by depolarization but prevented the inhibitory effect of protein kinase A activators. The action of dexamethasone had the hallmarks of protein induction, i.e. a lag time and sensitivity to inhibitors of DNA transcription and mRNA translation. In parallel, the specific BK channel blocker iberiotoxin abolished early glucocorticoid inhibition of corticotropin-releasing factor-stimulated ACTH secretion. In summary, the present data show that glucocorticoid-induced proteins render BK-type channels resistant to inhibition by protein kinase A and that this action of the steroid is pivotal for its early inhibitory effect on the secretion of ACTH.
Shipston
M J
MJ
Department of Pharmacology, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
Kelly
J S
JS
Antoni
F A
FA
D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology*; D005071:Evoked Potentials / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D007700:Kinetics; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018408:Patch-Clamp Techniques; D010903:Pituitary Gland, Anterior; D010911:Pituitary Neoplasms; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000502:physiology*; D024681:Potassium Channels, Calcium-Activated; D013873:Thionucleotides / Q000494:pharmacology
D005938:Glucocorticoids; D051036:Large-Conductance Calcium-Activated Potassium Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D013873:Thionucleotides; C016957:adenosine-3',5'-cyclic phosphorothioate; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases