Regulation of Caβ+-Activated K+ Currents by Ciglitazone in Rat Pituitary GH3 Cells

Abstract

Background

Ciglitazone, an antidiabetic agent of the thiazolidinedione family, is known to be an activator of the peroxisome-proliferator activator receptor (PPAR)-γ. The underlying mechanism of ciglitazone actions on ionic currents in neuroendocrine cells remains unclear.

Methods

The effects of ciglitazone on ionic currents were investigated in rat pituitary GH3 cells using the whole-cell and inside-out configurations of the patch-clamp technique.

Results

In GH3 cells, ciglitazone at 3–300 µmol/L caused a reversible increase in the amplitude of the Ca²⁺-activated K⁺ current (I_K(Ca)) with a half-maximal concentration of 16 µmol/L. Under the inside-out patch recording mode, ciglitazone applied intracellularly increased the activity of the large-conductance Ca²⁺-activated K⁺(BK_Ca) channels, but did not affect their single-channel conductance. However, troglitazone (30 µmol/L) caused a reduction in the channel activity. The ciglitazone-induced change in the kinetic behavior of BK_Ca channels is due to an increase in mean open time and a decrease in mean closed time, whereas the troglitazone-induced decrease 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 midpoint for voltage-dependent opening. The ciglitazone-stimulated activity of BK_Ca channels is independent of internal Ca²⁺. Under the current clamp mode, ciglitazone (30 µmol/L) hyperpolarized the membrane potential.

Conclusions

This study shows that in addition to its activation of PPAR-γ, ciglitazone can stimulate the activity of BK_Ca channels expressed in GH3 cells. These effects may affect membrane potentials and contribute to the ciglitazone-induced change in the functional activity of neurons or neuroendocrine cells.