Glucocorticoids stimulate the activity of large-conductance Ca2+-activated K+ channels in pituitary GH3 and AtT-20 cells via a non-genomic mechanism

The effects of glucocorticoids on ion currents were investigated in pituitary GH(3) and AtT-20 cells. In whole-cell configuration, dexamethasone, a synthetic glucocorticoid, reversibly increased the density of Ca2+-activated K+ current (I-K(Ca)) with an EC50 value of 21 +/- 5 mu M. Dexamethasone-induced increase in I-K(Ca) density was suppressed by paxilline (1 mu M), yet not by glibenclamide (10 mu M), pandinotoxin(-)Ka (1 mu M) or mifepristone (10 mu M). Paxilline is a blocker of large-conductance Call-activated K+ (BKCa) channels, while glibenclamide and pandinotoxin-K alpha are blockers of ATP-sensitive and A-type K+ channels, respectively. Mifepristone can block cytosolic glucocorticoid receptors. In inside-out configuration, the application of dexamethasone (30 mu M) into the intracellular surface caused no change in single-channel conductance; however, it did increase BKCa-channel activity. Its effect was associated with a negative shift of the activation curve. However, no Ca2+-sensitiviy of these channels was altered by dexamethasone. Dexamethasone-stimulated channel activity involves an increase in mean open time and a decrease in mean closed time. Under current-clamp configuration, dexamethasone decreased the firing frequency of action potentials. In pituitary AtT-20 cells, dexamethasone (30 mu M) also increased BKCa-channel activity. Dexamethasone-mediated stimulation of IK(Ca) presented here that is likely pharmacological, seems to be not linked to a genomic mechanism. The non-genomic, channel-stimulating properties of dexamethasone may partly contribute to the underlying mechanisms by which glucocorticoids affect neuroendocrine function.