Korean J Physiol Pharmacol.  2023 Jan;27(1):95-103. 10.4196/kjpp.2023.27.1.95.

Effects of rosiglitazone, an antidiabetic drug, on Kv3.1 channels

• Lee HM
• Yoon SH
• Kim MG
• Hahn SJ
• Choi BH

• KMID: 2537507
• DOI: http://doi.org/10.4196/kjpp.2023.27.1.95

Abstract

Rosiglitazone is a thiazolidinedione-class antidiabetic drug that reduces blood glucose and glycated hemoglobin levels. We here investigated the interaction of rosiglitazone with Kv3.1 expressed in Chinese hamster ovary cells using the wholecell patch-clamp technique. Rosiglitazone rapidly and reversibly inhibited Kv3.1 currents in a concentration-dependent manner (IC ₅₀ = 29.8 µM) and accelerated the decay of Kv3.1 currents without modifying the activation kinetics. The rosiglitazonemediated inhibition of Kv3.1 channels increased steeply in a sigmoidal pattern over the voltage range of –20 to +30 mV, whereas it was voltage-independent in the voltage range above +30 mV, where the channels were fully activated. The deactivation of Kv3.1 current, measured along with tail currents, was also slowed by the drug. In addition, the steady-state inactivation curve of Kv3.1 by rosiglitazone shifts to a negative potential without significant change in the slope value. All the results with the use dependence of the rosiglitazone-mediated blockade suggest that rosiglitazone acts on Kv3.1 channels as an open channel blocker.

Keyword

Open channel block; Potassium channels; Rosiglitazone; Shaw-type potassium channels

Figure

• 

  Fig. 1 Concentration-dependent inhibition of Kv3.1 currents by rosiglitazone. (A) Kv3.1 currents were generated with depolarization of +40 mV (300 ms) from a holding potential of –80 mV, every 10 sec. Currents recorded in the absence and presence of 3, 10, 30, and 100 µM rosiglitazone were superimposed. The dotted line represents zero current. (B) Dose-response curves of rosiglitazone-induced reduction in Kv3.1 currents. The amplitudes of Kv3.1 current were measured at the end (●) and peak (○) of the depolarizing pulses at various concentrations of rosiglitazone. The data of % inhibition (I (%) = [1 – Irosiglitazone / Icontrol] ×100) were fitted with the Hill equation (solid lines). (C) Time course of Kv3.1 inhibition by rosiglitazone. The current amplitudes were measured at the end of a 300-ms depolarizing pulse and normalized to the baseline amplitude. Data are expressed as mean ± SEM.

• 

  Fig. 2 Voltage dependence of rosiglitazone-mediated inhibition of Kv3.1 currents. The Kv3.1 currents were elicited by applying 300-ms depolarizing pulses between –50 and +70 mV in 10-mV increments every 10 sec from a holding potential of –80 mV under control conditions (A), and in the presence of 30 µM rosiglitazone (B). The dotted lines in (A) and (B) represent zero current. (C) The amplitudes of Kv3.1 currents were measured at the end of test pulses and plotted against membrane potentials, in control (○) and 30 µM rosiglitazone (●). (D) The activation curve of control Kv3.1 current was constructed from tail current amplitudes at –40 mV after 300-ms depolarizing pulses between –50 and +70 mV in 10 mV. Only the Boltzmann fitting curve is shown (dotted line, normalized current y-axis for activation curve). In order to compare with the activation profile, the percent inhibition of Kv3.1 current by rosiglitazone was plotted (■). The solid line was drawn from a linear curve fitted to the relative current data between +30 and +70 mV. Data are expressed as mean ± SEM.

• 

  Fig. 3 Concentration-dependent kinetics of Kv3.1 inhibition caused by rosiglitazone. (A) Superimposed Kv3.1 current traces were elicited with +40 mV pulses (300 ms) every 10 sec in the presence of rosiglitazone (10, 30, and 100 µM). The drug-induced time constants were obtained from a single exponential fitting to the decay traces of Kv3.1 currents (solid lines). The dotted line represents zero current. (B) Summary data obtained from A. The time constants (τ) were plotted against rosiglitazone concentrations (n = 4; *p < 0.05 vs. control data). Data are expressed as mean ± SEM.

• 

  Fig. 4 Effects of rosiglitazone on the deactivation kinetics of Kv3.1 currents. Tail currents were elicited with the 150-ms repolarizing pulse of –40 mV after a 300-ms depolarizing pulse of +40 mV, in the absence and presence of 30 µM rosiglitazone. Tail crossover (indicated by arrow) was observed by superimposing two tail currents. The dotted line represents zero current. Inset, the mean value of deactivation time constant (τ) in the presence of rosiglitazone was significantly greater than that in control condition (n = 4; *p < 0.05). Data are expressed as mean ± SEM.

• 

  Fig. 5 Use dependence of rosiglitazone-induced inhibition of Kv3.1. (A) Superimposed Kv3.1 current traces elicited successively with 8 repetitive depolarizing pulses (+40 mV, 300 ms) from a holding potential of –80 mV at 1 Hz in the absence and presence of 30 µM rosiglitazone. The dotted lines represent zero current. (B) Plot of normalized amplitudes of peak currents at 1 (circles) and 2 Hz (triangles), in control (open symbols) and in 30 µM rosiglitazone (closed symbols), against the elapsed time axis. The peak amplitudes were normalized to the peak amplitude of the first current in each condition. (C) With the data in (B), the current amplitude in the presence of rosiglitazone was normalized to the control amplitude at each elapsed time. Data are expressed as mean ± SEM.

• 

  Fig. 6 Effects of rosiglitazone on the steady-state inactivation of Kv3.1 currents. (A) The steady-state inactivation was analyzed using a two-pulse protocol. The currents were induced by a 300-ms pulse to +40 mV while 20-sec preconditioning pulses were varied from –60 to +30 mV using 10-mV steps every 30 sec in the absence and presence of 30 µM rosiglitazone. The dotted lines represent zero current. (B) The steady-state inactivation curves in control (○) and 30 µM rosiglitazone (●) were constructed by normalizing to the peak amplitude after a prepulse and by fitting each set of data with the Boltzmann equation. Data are expressed as means ± SEM.

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