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. 2017 May 15:1663:87-94.
doi: 10.1016/j.brainres.2017.03.009. Epub 2017 Mar 11.

Inhibition of Kir4.1 potassium channels by quinacrine

Leticia G Marmolejo-Murillo  1 , Iván A Aréchiga-Figueroa  2 , Meng Cui  3 , Eloy G Moreno-Galindo  1 , Ricardo A Navarro-Polanco  1 , José A Sánchez-Chapula  1 , Tania Ferrer  4 , Aldo A Rodríguez-Menchaca  5
Affiliations

Inhibition of Kir4.1 potassium channels by quinacrine

Leticia G Marmolejo-Murillo et al. Brain Res. .

Abstract

Inwardly rectifying potassium (Kir) channels are expressed in many cell types and contribute to a wide range of physiological processes. Particularly, Kir4.1 channels are involved in the astroglial spatial potassium buffering. In this work, we examined the effects of the cationic amphiphilic drug quinacrine on Kir4.1 channels heterologously expressed in HEK293 cells, employing the patch clamp technique. Quinacrine inhibited the currents of Kir4.1 channels in a concentration and voltage dependent manner. In inside-out patches, quinacrine inhibited Kir4.1 channels with an IC50 value of 1.8±0.3μM and with extremely slow blocking and unblocking kinetics. Molecular modeling combined with mutagenesis studies suggested that quinacrine blocks Kir4.1 by plugging the central cavity of the channels, stabilized by the residues E158 and T128. Overall, this study shows that quinacrine blocks Kir4.1 channels, which would be expected to impact the potassium transport in several tissues.

Keywords: Cationic amphiphilic drugs; Kir4.1 channels; Quinacrine.

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Figures

Figure 1
Figure 1
Effect of quinacrine (Qn) on Kir4.1 channels expressed in HEK293 cells and recorded under whole-cell configuration. (A–B) Representative Kir4.1 current traces in absence (control) and presence of 3 (A) and 30 μM (B) Qn. Here and hereafter, dotted lines define the zero current level. (C) Average steady-state I–V curves in the absence and presence of Qn at the indicated concentrations (n=5). (D) Representative Kir4.1 current traces elicited by a 2 s depolarizing pulse followed by a long (20 s) repolarizing pulse in absence (control) and presence of 30 μM Qn.
Figure 2
Figure 2
Effect of Qn on Kir4.1 channels expressed in HEK293 cells and recorded in excised inside-out patches. (A–C) Representative Kir4.1 current traces in absence (control) and presence of 1 (A), 10 (B) and 100 μM (C) Qn. (D) Concentration-response curve of the Qn fractional block at +80 mV (n=5–10).
Figure 3
Figure 3
Blocking and unblocking kinetics of Kir4.1 currents by 30 and 100 μM Qn. (A) Current ratios (Idrug/Icontrol) with 30 (red trace) and 100 μM (black trace) Qn generated from recordings like those shown in the inset. Cells were held at −80 mV and stepped to +80 mV followed by a repolarization to −80 mV. (B) Time constants of Qn blockade of Kir4.1 currents. (C) Unblocking time constants of Qn. (n = 5) *p<0.05, **p<0.01.
Figure 4
Figure 4
Qn block is altered by mutations in the central cavity of Kir4.1 channels. Representative Kir4.1WT (A), Kir4.1T127A (B), Kir4.1T128A (C) and Kir4.1E158N (D) current traces in absence (control) and presence of 10 μM Qn. (E) Percentage of inhibition of Kir4.1 currents by 10 μM Qn. (n= 4–6) *p<0.05, **p<0.01.
Figure 5
Figure 5
Molecular model of Kir4.1 channel binding pocket with docked Qn. The Kir4.1 channel model is shown in NewCartoon presentation (subunits A, B, and D are in blue, yellow, and orange, respectively. The subunit C was removed for clarity). The Qn is drawn in Licorice, and interacting residues with Qn are drawn in VDW sphere.
See this image and copyright information in PMC

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