Abstract
Earlier studies have demonstrated that the tandem pore domain weak inward rectifying K+ channel (TWIK)-related K+ (TREK)-1 channel is inhibited by antidepressants and is associated with major depression. However, little is known about the effect of mood stabilizers that are commonly used for treatment of bipolar disorder on TREK channels, members of the two-pore domain K+ (K2P) channel family. This study sought to investigate the effect of mood stabilizers on TREK-1 and TREK-2 channels. HEK-293A cells were transfected with human TREK-1 or TREK-2 DNA. The effect of mood stabilizers on TREK-1 and TREK-2 was studied using the patch clamp technique. Changes in TREK protein expression by mood stabilizers were studied in the HT-22 mouse hippocampal neuronal cells using western blot analysis. Lithium chloride (LiCl, 1 mM), gabapentin (100 μM), valproate (100 μM), and carbamazepine (100 μM) increased TREK-1 currents by 31 ± 14%, 25 ± 11%, 28 ± 12%, and 72 ± 12%, respectively, whereas they had no effect on TREK-2 channel activity. In addition, western blot analysis showed LiCl and carbamazepine slightly upregulated TREK-1 expression, but not TREK-2 in the HT-22 cells. These results suggest that TREK-1 could be a potential therapeutic target for treatment of bipolar disorders as well as depression, while TREK-2 is a target well suited for treatment of major depression.
Highlights
IntroductionTWIK-related K+ (TREK)-1 and TREK-2 channels, members of the two-pore domain K+ (K2P) channel family, are inhibited by antidepressants (fluoxetine, norfluoxetine, and paroxetine) and antipsychotics (fluphenazine, chlorpromazine, haloperidol, flupenthixol, loxapine, and pimozide) in a concentration-dependent and reversible manner [1,2,3,4]
TWIK-related K+ (TREK)-1 and TREK-2 channels, members of the two-pore domain K+ (K2P) channel family, are inhibited by antidepressants and antipsychotics in a concentration-dependent and reversible manner [1,2,3,4]
We have shown that both TREK-1 and TREK-2 currents are inhibited by several antidepressants and antipsychotics with IC50 values of ~40 μM, in agreement with earlier studies [2,3,19]
Summary
TWIK-related K+ (TREK)-1 and TREK-2 channels, members of the two-pore domain K+ (K2P) channel family, are inhibited by antidepressants (fluoxetine, norfluoxetine, and paroxetine) and antipsychotics (fluphenazine, chlorpromazine, haloperidol, flupenthixol, loxapine, and pimozide) in a concentration-dependent and reversible manner [1,2,3,4]. The TREK-1 channel has been presented as a new potential therapeutic target for the treatment of depression, as it is the first ion channel implicated in the pathophysiology of depression [3,5,6]. TREK-1 and TREK-2 share similar biophysical and pharmacological properties in a variety of cells [7]. Relatively little attention has been focused on TREK-2. At this point, we sought to ask whether both TREK-1 and TREK-2 channels (TREKs) could be involved in mania as well as depression
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