Abstract
Various antidepressants are commonly used for the treatment of depression and several other neuropsychiatric disorders. In addition to their primary effects on serotonergic or noradrenergic neurotransmitter systems, antidepressants have been shown to interact with several receptors and ion channels. However, the molecular mechanisms that underlie the effects of antidepressants have not yet been sufficiently clarified. G protein-activated inwardly rectifying K+ (GIRK, Kir3) channels play an important role in regulating neuronal excitability and heart rate, and GIRK channel modulation has been suggested to have therapeutic potential for several neuropsychiatric disorders and cardiac arrhythmias. In the present study, we investigated the effects of various classes of antidepressants on GIRK channels using the Xenopus oocyte expression assay. In oocytes injected with mRNA for GIRK1/GIRK2 or GIRK1/GIRK4 subunits, extracellular application of sertraline, duloxetine, and amoxapine effectively reduced GIRK currents, whereas nefazodone, venlafaxine, mianserin, and mirtazapine weakly inhibited GIRK currents even at toxic levels. The inhibitory effects were concentration-dependent, with various degrees of potency and effectiveness. Furthermore, the effects of sertraline were voltage-independent and time-independent during each voltage pulse, whereas the effects of duloxetine were voltage-dependent with weaker inhibition with negative membrane potentials and time-dependent with a gradual decrease in each voltage pulse. However, Kir2.1 channels were insensitive to all of the drugs. Moreover, the GIRK currents induced by ethanol were inhibited by sertraline but not by intracellularly applied sertraline. The present results suggest that GIRK channel inhibition may reveal a novel characteristic of the commonly used antidepressants, particularly sertraline, and contributes to some of the therapeutic effects and adverse effects.
Highlights
Depression is one of the most common illnesses in the world [1,2]
Inhibition of G protein-activated inwardly rectifying K+ (GIRK) channels by antidepressants In Xenopus oocytes injected with GIRK1 and GIRK2 mRNAs, basal GIRK currents, which depend on free G-protein bc subunits present in the oocytes because of the inherent activity of Gproteins [32], were observed at a holding potential of 270 mV in an hK solution that contained 96 mM K+ (Fig. 1A)
The present study demonstrated that the SSRI sertraline, serotonin-norepinephrine reuptake inhibitors (SNRIs) duloxetine, and second-generation tricyclic antidepressants (TCAs) amoxapine effectively inhibited brain-type GIRK1/2 channels and cardiac-type GIRK1/4 channels expressed in Xenopus oocytes
Summary
Depression is one of the most common illnesses in the world [1,2]. After the efficacy of tricyclic antidepressants (TCAs), including imipramine, amitriptyline and amoxapine, was well established, various classes of antidepressants were introduced, including selective serotonin reuptake inhibitors (SSRIs; fluoxetine, paroxetine and sertraline), serotonin-norepinephrine reuptake inhibitors (SNRIs; venlafaxine and duloxetine), selective norepinephrine reuptake inhibitors (NRIs; reboxetine), noradrenergic and specific serotonergic antidepressants (NaSSAs; mirtazapine and mianserin), and 5-hydroxytryptamine type 2 (5-HT2) receptor antagonists (nefazodone) [1,2,3]. Antidepressants are commonly used for the treatment of depression and several neuropsychiatric disorders, such as anxiety disorders, eating disorders, obsessive-compulsive disorders, and chronic pain disorders [1,2,3]. Their clinical efficacy is hypothesized to be linked mainly with facilitation of noradrenergic or serotonergic function in the brain [2]. The modulation of these receptors and channels might be relevant to the pharmacological effects of antidepressants
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