Pioglitazone, a PPAR-γ Activator, Stimulates BKCa but Suppresses IKM in Hippocampal Neurons

Pioglitazone (PIO), a thiazolidinedone, was reported to stimulate peroxisome proliferator-activated receptor-γ (PPAR-γ) with anti-inflammatory, anti-proliferative, anti-diabetic, and antidepressive activities. However, whether this compound exerts any perturbations on Ca 2+ -activated K + and M-type K + currents in central neurons remains largely unresolved. In this study, we investigated the effects of PIO on these potassium currents in hippocampal neurons (mHippoE-14). In whole-cell current recordings, the presence of PIO (10 μM) increased the amplitude of Ca 2+ -activated K + current [ I K(Ca) ] in mHippoE-14 cells. PIO-induced stimulation of I K(Ca) observed in these cells was reversed by subsequent addition of paxilline, yet not by TRAM-39 or apamin. In inside-out current recordings, PIO applied to the bath concentration-dependently increased the activity of large-conductance Ca 2+ -activated K + (BK Ca ) channels with an EC 50 value of 7.6 μM. Its activation of BK Ca channels in mHippoE-14 cells was voltage-dependent and accompanied by both a lengthening in mean open time and a shortening in slow component of mean closed time. The activation curve of BK Ca channels after addition of PIO was shifted to less depolarized potential without any change in the gating charge. PIO also suppressed the amplitude of M-type K + currents inherently in mHippoE-14 neurons. Taken together, in addition to its agonistic action on PPAR-γ, PIO-induced perturbation of these potassium channels may be responsible for its widely pharmacological actions on hippocampal neurons.