Regulation of Ca2+-activated K+ currents by ciglitazone in rat pituitary GH(3) cells

Background: Ciglitazone, an antidiabetic agent of the thiazolidinedione fam ily, is known to be an activator of the peroxisome-proliferator activator r eceptor (PPAR)-gamma. The underlying mechanism of ciglitazone actions on io nic currents in neuroendocrine cells remains unclear. Methods: The effects of ciglitazone on ionic currents were investigated in rat pituitary GH(3) cells using the whole-cell and inside-nut configuration s of the patch-clamp technique. Results: In GH, cells, ciglitazone at 3-300 mu mol/L caused a reversible in crease in the amplitude of the Ca2+-activated K+ current (I-K(Ca)) with a h alf-maximal concentration of 16 mu mol/L. Under the inside out patch record ing mode, ciglitazone applied intracellularly increased the activity of the large conductance Ca2+-activated K+ (BKCa) channels, but did not affect th eir single-channel conductance. However, troglitazone (30 mu mol/L) caused a reduction in the channel activity. The ciglitazone-induced change in the kinetic behavior of BKCa channels is due to an increase in mean open time a nd a decrease in mean closed time, whereas the troglitazone-induced decreas e in the channel activity is related to a decrease in mean open time and an increase in mean closed time. Ciglitazone caused a left shift in the midpo int for voltage-dependent opening. The ciglitazone-stimulated activity of B KCa channels is independent of internal Ca2+. Under the current clamp mode, ciglitazone (30 mu mol/L) hyperpolarized the membrane potential. Conclusions: This study shows that in addition to its activation of PPAR-ga mma, ciglitazone can stimulate the activity of BKCa channels expressed in G H(3) cells. These effects may affect membrane potentials and contribute to the ciglitazone-induced change in the functional activity of neurons or neu roendocrine cells.