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

Abstract

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 Ca2+-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 Ca2+-activated K+ current [IK(Ca)] in mHippoE-14 cells. PIO-induced stimulation of IK(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 Ca2+-activated K+ (BKCa) channels with an EC50 value of 7.6 μM. Its activation of BKCa 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 BKCa 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.

Effectiveness of nalbuphine, a κ‐opioid receptor agonist and μ‐opioid receptor antagonist, in the inhibition of INa, IK(M), and IK(erg) unlinked to interaction with opioid receptors

“…The activity of BK Ca channels has been reported to be present in mHippoE‐14 neurons (Chen et al, ). Morphine‐induced hyperalgesia has been demonstrated to be linked to the increase in BK Ca ‐channel activity (Hayashi et al, ).…”

“…Alternatively, subsequent addition of pioglitazone (10 μM) on the intracellular surface of the excised patch increased the probability of BK Ca ‐channel openings to 0.029 ± 0.008 ( n = 8, p < .05). Pioglitazone has been reported to activate BK Ca channels (Chen et al, ; Hung, Chu, Wu, Wu, & Huang, ). However, in this study, NAL was found to be unable to modify the activity of BK Ca channels in mHippoE‐14 neurons.…”

“…Embryonic mouse hippocampal cell line (HippoE‐14; CLU198) was obtained from Cedarlane CELLutions Biosystems, Inc. (Burlington, ON, Canada) (Gingerich et al, ). The cells were maintained at a density of 10 6 /ml in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% (v/v) heat‐inactivated fetal bovine serum (FBS) and 2 mM L‐glutamine (Chen et al, ). They were grown as a monolayer culture in 50‐ml plastic culture flasks in a humidified 5% CO 2 /95% air environment at 37°C.…”

“…The mHippoE‐14 hippocampal cell line is recognized to possess the characteristics of embryonic hippocampal neurons and useful for new therapeutics targeted to neurological disorders (Chen et al, ; Gingerich et al, ; Hsiao, Liu, Liu, & Wu, ). Earlier studies have reported the expression of μ‐ or κ‐opioid receptors in hippocampal cells (Chen et al, ).…”

Total flavones of Rhododendron simsii Planch flower protect rat hippocampal neuron from hypoxia-reoxygenation injury via activation of BKCa channel

“…A noise‐like outward current of BK Ca channel was evoked in the primary cultured rat hippocampal neurons. This is in agreement with a previous study in the embryonic mouse hippocampal neurons . In the range of 33.3–300 mg/l, TFR significantly increased the current of neuronal BK Ca channel in a concentration‐dependent manner, which could be inhibited by IBTX, a specific blocker of BK Ca channel.…”