Open Channel Block of A-Type, K_v4.3, and Delayed Rectifier K⁺ Channels, K_v1.3 and K_v3.1, by Sibutramine

Abstract

The effects of sibutramine on voltage-gated K ϩ channel (K v )4.3, K v 1.3, and K v 3.1, stably expressed in Chinese hamster ovary cells, were investigated using the whole-cell patch-clamp technique. Sibutramine did not significantly decrease the peak K v 4.3 currents, but it accelerated the rate of decay of current inactivation in a concentration-dependent manner. This phenomenon was effectively characterized by integrating the total current over the duration of a depolarizing pulse to ϩ40 mV. The IC 50 value for the sibutramine block of K v 4.3 was 17.3 M. Under control conditions, the inactivation of K v 4.3 currents could be fit to a biexponential function, and the time constants for the fast and slow components were significantly decreased after the application of sibutramine. The association (k ϩ1 ) and dissociation (k Ϫ1 ) rate constants for the sibutramine block of K v 4.3 were 1.51 M Ϫ1 s Ϫ1 and 27.35 s Ϫ1 , respectively. The theoretical K D value, derived from k Ϫ1

Rosiglitazone inhibits Kv4.3 potassium channels by open‐channel block and acceleration of closed‐state inactivation

“…The lack of change in deactivation kinetics of Kv4.3 channels might indicate that 'unblocking' of the channel was not necessary for channel closing and the drug could be trapped in the deactivated channels. This phenomenon is similar to the situations described for other open channel block of Kv4.3 and Kv1.5 channels (Lacerda et al, 1997;Kim et al, 2007).…”

“…Figure 1A shows the superimposed Kv4.3 channel currents that resulted from a 500 ms depolarizing pulse to +40 mV under control conditions and in the presence of rosiglitazone. Under control conditions, the Kv4.3 currents were activated to maximum and then were rapidly inactivated as reported previously (Ohya et al, 1997;Ahn et al, 2006;Kim et al, 2007). Rosiglitazone not only reduced the peak amplitude of the Kv4.3 currents but also altered the time course of the current decay.…”

Amoxapine Inhibits the Delayed Rectifier Outward K+ Current in Mouse Cortical Neurons via cAMP/Protein Kinase A Pathways

“…It was previously reported that externally applied TCAs inhibit ion channel activity by binding to an extracellular site or by diffusing through the cell membrane to gain access to a binding site on the internal surface of the membrane (Kuo, 1998;Kim et al, 2007). However, our results argue against direct I K blocking activity.…”

“…Although the mechanism by which TCAs can affect ion channel activity has not been elucidated, previous reports have suggested a direct interaction between the drugs and the ion channels (Kim et al, 2007). It was reported that the drugs can block ion channel conductance by binding within the pore itself or by allosteric inhibition produced by binding outside the pore.…”

Inhibition of Kv4.3 by genistein via a tyrosine phosphorylation-independent mechanism

“…Figure 1A shows the superimposed Kv4.3 currents expressed in CHO cells under control conditions and in the presence of various concentrations of genistein. Under control conditions, Kv4.3 currents were activated to a peak and then were rapidly inactivated during a 500-ms pulse of ϩ40 mV at 10-s intervals, as described previously (2,22,30). In the presence of genistein, inhibition of Kv4.3 currents was substantiated by a concentration-dependent reduction in peak current amplitude.…”