Korean J Physiol Pharmacol.  2016 Mar;20(2):193-200. 10.4196/kjpp.2016.20.2.193.

Blockade of Kv1.5 channels by the antidepressant drug sertraline

• Lee HM
• Hahn SJ
• Choi BH

• KMID: 2388676
• DOI: http://doi.org/10.4196/kjpp.2016.20.2.193

Abstract

Sertraline, a selective serotonin reuptake inhibitor (SSRI), has been reported to lead to cardiac toxicity even at therapeutic doses including sudden cardiac death and ventricular arrhythmia. And in a SSRI-independent manner, sertraline has been known to inhibit various voltage-dependent channels, which play an important role in regulation of cardiovascular system. In the present study, we investigated the action of sertraline on Kv1.5, which is one of cardiac ion channels. The eff ect of sertraline on the cloned neuronal rat Kv1.5 channels stably expressed in Chinese hamster ovary cells was investigated using the whole-cell patch-clamp technique. Sertraline reduced Kv1.5 whole-cell currents in a reversible concentration-dependent manner, with an IC50 value and a Hill coefficient of 0.71 microM and 1.29, respectively. Sertraline accelerated the decay rate of inactivation of Kv1.5 currents without modifying the kinetics of current activation. The inhibition increased steeply between -20 and 0 mV, which corresponded with the voltage range for channel opening. In the voltage range positive to +10 mV, inhibition displayed a weak voltage dependence, consistent with an electrical distance delta of 0.16. Sertraline slowed the deactivation time course, resulting in a tail crossover phenomenon when the tail currents, recorded in the presence and absence of sertraline, were superimposed. Inhibition of Kv1.5 by sertraline was use-dependent. The present results suggest that sertraline acts on Kv1.5 currents as an open-channel blocker.

Keyword

Kv1.5; Open channel block; Selective serotonin reuptake inhibitor; Sertraline; Shaker-type K+ channel

MeSH Terms

Animals
Arrhythmias, Cardiac
Cardiovascular System
Clone Cells
Cricetinae
Cricetulus
Death, Sudden, Cardiac
Female
Inhibitory Concentration 50
Ion Channels
Kinetics
Neurons
Ovary
Patch-Clamp Techniques
Rats
Serotonin
Sertraline*
Tail
Ion Channels
Serotonin
Sertraline

Figure

• 

  Fig. 1 Concentration-dependent inhibition of Kv1.5 by sertraline.(A) Superimposed current traces were produced by applying 250-ms depolarizing pulses from a holding potential of –80 to +50 mV followed by a 250-ms repolarizing pulse to –40 mV every 10 s under control conditions and in the presence of 0.3, 1, 3 and 10 µM sertraline, as indicated. The dotted line represents zero current. (B) Concentration-dependent curve of inhibition by sertraline. Current amplitudes of Kv1.5 measured at the end of the depolarizing pulses were used and the percentage inhibitions were plotted against various concentrations of sertraline. The solid line is fitted to the data points by the Hill equation. Data are expressed as mean±S.E.M. (C) Representative time course for inhibition in the presence of 1 µM sertraline. The current amplitudes were measured at the end of a 250-ms depolarizing pulses from a holding potential of –80 to +50 mV every 10 s in the presence of 1 µM sertraline and normalized to the first current amplitude and the normalized data were plotted as a function of time.

• 

  Fig. 2 Voltage dependent inhibition of Kv1.5 currents by sertraline.The Kv1.5 currents were produced by applying 250-ms pulses between –60 and +50 mV in 10-mV increments followed by a 250-ms repolarizing pulse to –40 mV every 10 s, from a holding potential of –80 mV under control conditions (A), and after the addition of 1 µM sertraline (B). The dotted lines in (A) and (B) represent zero current. (C) Resultant I~V relationships taken at the end of the test pulses in the absence (open circle) and presence (closed circle) of 1 µM sertraline. (D) Percentage current inhibition (closed square) from data in (C) was plotted against the membrane potential. For potentials positive to +10 mV, the data of percentage current inhibition was recalculated by using ln{(IControl–ISertraline)/ISertraline} (closed triangle) and replotted against membrane potential. The voltage dependence was linear fitted with equation 4 (see METHODS), shown by the solid line with the indicated values for the equivalent electrical distance (δ=0.16±0.03, n=4). The dotted line represents the activation curve of Kv1.5 under control conditions, which was obtained from a deactivating tail current amplitude at –40 mV after 250-ms depolarizing pulses to potentials between –60 to +50 mV in steps of 10 mV from a holding potentials of –80 mV and thereafter normalization using equation 2 (see METHODS).

• 

  Fig. 3 Concentration-dependent kinetics of Kv1.5 inhibition by sertraline.(A) Superimposed Kv1.5 current traces were elicited by applying 250-ms depolarizing pulses from a holding potential of –80 to +50 mV every 10 s in the presence of sertraline (1, 3, and 10 µM). The drug-induced time constants were obtained by a single exponential fitting to the decaying traces of Kv1.5 currents. The dotted line represents zero current. (B) Summary data obtained from (A). The time constants (τ) were plotted versus various concentrations of sertraline (n =4; *p<0.05 versus control data). Data are expressed as mean±S.E.M.

• 

  Fig. 4 Effects of sertraline on deactivation kinetics of Kv1.5.(A) Tail currents were induced at the repolarizing pulses of –40 mV after a 250-ms depolarizing pulse of +50 mV from a holding potential of –80 mV in the absence and presence of 1 µM sertraline. The dotted lines represent a zero current. Tail crossover phenomenon (indicated by the arrow) observed by superimposing the two tail currents. The solid lines over the current traces represent the single exponential fitting to the data. (B) Deactivation time constants (π) obtained from (A). The symbol *indicates a statistically significant difference (n=4, p<0.05 versus control data). Data are expressed as mean±S.E.M.

• 

  Fig. 5 Effects of repetitive depolarization on sertraline-induced inhibition of Kv1.5 currents.(A) Original current traces under control conditions and in the presence of 1 µM sertraline obtained from applying 20 repetitive 125-ms depolarizing pulses of +50 mV from a holding potential of –80 mV at 1 or 2 Hz. The dotted lines represent a zero current. (B) Plot of normalized current at two different frequencies, 1 and 2 Hz under control conditions (open circle and open triangle, n=4) and in the presence of 1 µM sertraline (closed circle and closed triangle, n=4) as a function of the number of pulses. The peak amplitudes of the current at every pulse were normalized to the peak amplitudes of current obtained at the first pulse. (C) Relative current (ISertraline/IControl) plotted at 1 (open square) and 2 Hz (closed square) from (B) as a function of the number of pulses. Data are expressed as mean±S.E.M.

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