Blockade of Kv1.5 channels by the antidepressant drug sertraline

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 µM 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 δ 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.

Facilitation of serotonin-induced contraction of rat mesenteric artery by ketamine

“…Our preliminary observation is that ketamine increases the phosphorylation of src in the presence of low concentrations of 5-HT (~30 nM), which suggests that ketamine may facilitate the src activation process after 5-HT 2A receptor activation. It is also interesting that some selective serotonin reuptake inhibitors (SSRIs), which are frequently used for treating mood disorders and work by increasing 5-HT concentrations in the synaptic spaces of the central nervous system, are reported to block Kv channels, such as Kv1.5 [2930], which are the downstream targets of 5-HT 2A receptors [1925]. …”

Post-SSRI Sexual Dysfunction: A Bioelectric Mechanism?

“…This could be due to effects on the electrogenic serotonin transporter SERT or perhaps upon one or more of several ion channels. [60][61][62][63][64] Because the basic bioelectric circuitry is highly conserved, animal models can serve as an important context within which to understand clinically relevant persistent physiological states induced by transient drug exposure. Thus, we examined the possibility of SSRI-induced long-term changes, which could provide a mechanism for the post-SSRI syndrome in human patients, in a tractable model system: planaria.…”

Challenges Faced with Small Molecular Modulators of Potassium Current Channel Isoform Kv1.5

“…To date, various kinds of Kv1.5 modulators have been disclosed, herein, we summarize the molecular structures and functionality of different types of Kv1.5 modulators with their chemical structure as follows (Table 1, Figure 2). As shown in Table 1, the existing Kv1.5 modulators can be divided into four categories: clinical cardiovascular drugs (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14), other clinical drugs (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28), drugs in development (29)(30)(31)(32)(33)(34)(35)(36)(37), and natural products (38)(39)(40)(41)(42)(43)(44)(45)(4...…”

“…A variety of natural products have been proven to modulate Kv1.5, but the exploration of novel skeleton could be helpful for the current dilemma. Among the isolated compounds, the main types are terpenoids (38)(39)(40)(41), alakaloids (42)(43)(44)(45)(46)(47), and flavonoids (48)(49)(50). Terpenoids are widely reported to inhibit potassium channels [26][27][28], however, the stability and difficulty in preparation because of the lack of a fluorescence group and the abundance in chiral carbon are worth worrying about in the development.…”