GLUCOCORTICOIDS BLOCK PROTEIN-KINASE A INHIBITION OF CALCIUM-ACTIVATED POTASSIUM CHANNELS

Adrenal corticosteroids have well known and profound effects on neuron s and neuroendocrine cells, but the underlying cellular mechanisms are poorly understood, The present study analyzed membrane currents and A CTH release in AtT20 mouse pituitary corticotrope tumor cells, Patch-c lamp analysis revealed a significant and selective inhibition of calci um-activated (BK-type) potassium channels upon activation of protein k inase 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 ha llmarks of protein induction, i.e. a lag time and sensitivity to inhib itors of DNA transcription and mRNA translation. In parallel, the spec ific BK channel blocker iberiotoxin abolished early glucocorticoid inh ibition of corticotropin-releasing factor-stimulated ACTH secretion, I n summary, the present data show that glucocorticoid-induced proteins render BK-type channels resistant to inhibition by protein kinase A an d that this action of the steroid is pivotal for its early inhibitory effect on the secretion of ACTH.