Open Channel Block of Kv3.1 Currents by Fluoxetine

Sung, Myongsoon; Ahn, Hyo–Suk; Hahn, Sang June; Choi, Bok Hee

doi:10.1254/jphs.fp0070759

Cited by 41 publications

(29 citation statements)

References 34 publications

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“…This is consistent with the actions of psoralen on the open state of Kv3.1 (Choi et al, 1999;Choi et al, 2001;Sung et al, 2008).…”

Section: Figsupporting

confidence: 88%

“…4) Psoralen slowed the deactivation time course, resulting in a tail crossover phenomenon. This latter phenomenon suggests an interaction between psoralen and the open state of Kv3.1 (Choi et al, 1999;Choi et al, 2001;Sung et al, 2008). 5) The actions of psoralen in inhibiting Kv3.1 were use-dependent, with effects enhanced at higher rates of channel and k are 9.7 ± 3.5 mV and 12.5 ± 1.9 mV, respectively (n = 4).…”

Section: Discussionmentioning

confidence: 96%

“…2A shows the superimposed-original Kv3.1 current traces obtained by 300-ms depolarizing pulse to +40 mV under control conditions and in the presence of various concentrations of psoralen. Under control conditions, Kv3.1 currents rapidly activated and then inactivated slightly during a 300-ms pulse of +40 mV, as described previously (Kanemasa et al, 1995;Sung et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

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Effect of psoralen on the cloned Kv3.1 currents

2009

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The psoralen, a furocoumarin derivative, on the cloned neuronal rat Kv3.1 channels stably expressed in Chinese hamster ovary cells was investigated using the whole-cell patch-clamp technique. Psoralen reduced Kv3.1 whole-cell currents in a reversible concentration-dependent manner, with an IC50 value and a Hill coefficient of 2.3 +/- 0.03 microM and 0.9 +/- 0.08, respectively. Psoralen accelerated the decay rate of inactivation of Kv3.1 currents without modifying the kinetics of current activation. The psoralen-induced inhibition of Kv3.1 channels was voltage-dependent, with a steep increase over the voltage range of channel opening. However, the inhibition exhibited voltage independence over the voltage range in which channels are fully activated. Psoralen slowed the deactivation time course, resulting in a tail crossover phenomenon when the tail currents, recorded in the presence and absence of psoralen, were superimposed. Inhibition of Kv3.1 by psoralen was use-dependent at a frequency of 1 Hz. The present results suggest that psoralen acts on Kv3.1 currents as an open-channel blocker.

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“…This is consistent with the actions of psoralen on the open state of Kv3.1 (Choi et al, 1999;Choi et al, 2001;Sung et al, 2008).…”

Section: Figsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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Effect of psoralen on the cloned Kv3.1 currents

2009

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“…Usedependent inhibition is a feature of open channel blockers, because when channels open more frequently, blockers have a higher chance of binding to channel pores. 16,20,24) Taken together, the results are consistent with fluvoxamine acting on the open state of Kv1.5 and suggest that fluvoxamine acts as an open channel blocker of Kv1.5. However, the several data were not consistent with the pure open-channel blocking scheme based on the following lines of evidence.…”

Section: Use-dependent Inhibition Of Kv15 By Fluvoxaminesupporting

confidence: 73%

Inhibitory Action of Fluvoxamine on Kv1.5 Currents

Lee

Hahn

Choi

2010

Biological & Pharmaceutical Bulletin

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Fluvoxamine is a selective serotonin reuptake inhibitor that exerts antidepressant activity by inhibiting the reuptake of serotonin, or 5-hydroxytryptamine, in the central nervous system. Fluvoxamine shows negligible affinity for other neurotransmitter reuptake systems, [1][2][3][4] so it may have advantages over other antidepressants in the treatment of depression. For example, tricyclic antidepressant (TCA) is associated with an increased risk of cardiovascular events. [5][6][7][8][9] However, accumulating evidence suggests that fluvoxamine may increase cardiovascular risk through inhibition of the human ether-a-go-go related (HERG) potassium channel. 10)The drug may also be associated with ventricular arrhythmia.11) Pharmacological blockade of cardiac muscle voltage-gated K ϩ channels (Kv channels) is associated with adverse cardiac arrhythmias, suggesting that fluvoxamine may interact with cardiac Kv channels. However, the exact effects of fluvoxamine on cardiac Kv channels remain to be elucidated.Kv1.5 is a cardiovascular-specific Kv channel isoform. It has an important role in determining the length of cardiac action potentials, and is a target of antiarrhythmic drugs. 12)Kv1.5 is rapidly activated and is difficult to inactivate, so it contributes to the repolarization of atrial action potentials. Kv1.5 dysfunction results in prolonged cardiac action potentials, eventually leading to cardiac arrhythmias with serious morbidity. [13][14][15] In this study, we investigated whether fluvoxamine interacts with Kv1.5 cloned from rat brain and determined the mechanisms by which fluvoxamine acts on Kv1.5. MATERIALS AND METHODS Stable Transfection and Cell CultureChinese hamster ovary (CHO) cells expressing Kv1.5 channels from rat brain were used for electrophysiological recordings.16) Kv1.5 cDNA 17) was cloned into the plasmid expression vector pCR3.1 (Invitrogen Corp., San Diego, CA, U.S.A.). CHO cells were transfected with Kv1.5 cDNA using FuGENE6 reagent (Boehringer Mannheim, Indianapolis, IN, U.S.A.).Transfected cells were cultured in Iscove's modified Dulbecco's medium (Invitrogen Corp.) supplemented with 10% fetal bovine serum, 2 mM glutamine, 0.1 mM hypoxanthine, 0.01 mM thymidine, and 300 mg/ml G418 (A.G. Scientific, San Diego, CA, U.S.A.) in 95% humidified air-5% CO 2 at 37°C. Cultures were passaged every 4-5 d by brief trypsinethylenediaminetetraacetic acid treatment, seeded onto glass coverslips (diameter: 12 mm, Fisher Scientific, Pittsburgh, PA, U.S.A.) in a Petri dish, and used for electrophysiological recordings after 12-24 h.Electrophysiological Recordings Kv1.5 currents were recorded from CHO cells using a whole-cell patch-clamp technique 18) at room temperature (22-23°C). Micropipettes fabricated from glass capillary tubing (PG10165-4; World Precision Instruments, Sarasota, FL, U.S.A.) with a doublestage vertical puller (PC-10; Narishige, Tokyo) had a tip resistance of 2-3 MW when filled with pipette solution. Wholecell currents were amplified with a MultiClamp 700B amplifier (Molecular Devices, S...

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“…Recent proposals of the mechanism of action suggest the interaction of antidepressants with K+ channels. Based on the findings that many antidepressants block K+ channels (Sung et al 2008; Ohno et al 2007; Wooltorton and Mathie, 1993; Yeung et al, 1999; Choi et al, 1999), the blockade of neuronal K-channels has been proposed as part of a mechanism for AGN 2979 antidepressant-like action (Gittos and Papp, 2001). Similarly, the selective serotonin reuptake inhibitors, paroxetine, sertraline, and fluoxetine, have potent K-channel blocking properties (Velasco et al, 1995, Yeung et al, 1999), similar to tricyclic anti-depressants (Wooltorton and Mathie, 1993).…”

Section: Discussionmentioning

confidence: 99%

AGN-2979, an inhibitor of tryptophan hydroxylase activation, does not affect serotonin synthesis in Flinders Sensitive Line rats, a rat model of depression, but produces a significant effect in Flinders Resistant Line rats

Kanemaru

Nishi

Dikšić

2009

Neurochemistry International

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The neurotransmitter, serotonin, is involved in several brain functions, including both normal, physiological functions, and pathophysiological functions. Alterations in any of the normal parameters of serotonergic neurotransmission can produce several different psychiatric disorders, including major depression. In many instances, brain neurochemical variables are not able to be studied properly in humans, thus making the use of good animal models extremely valuable. One of these animal models is the Flinders Sensitive Line (FSL) of rats, which has face, predictive and constructive validities in relation to human depression. The objective of this study was to quantify the effect of the tryptophan hydroxylase (TPH) activation inhibitor, AGN-2979, on the FSL rats (rats with depression-like behaviour), and compare it to the effect on the Flinders Resistant Line (FRL) of rats used as the control rats. The effect was evaluated by measuring changes in regional serotonin synthesis in the vehicle treated rats (FSL-VEH and FRL-VEH) relative to those measured in the AGN-2979 treated rats (FSL-AGN and FRL-AGN). Regional serotonin synthesis was measured autoradiographically in more than thirty brain regions. The measurements were performed using α-[ 14 C]methyl-L-tryptophan as the tracer. The results indicate that AGN-2979 did not produce a significant reduction of TPH activity in the AGN-2979 group relative to the vehicle group (a reduction would have been observed if there had been an activation of TPH by the experimental set up) in the FSL rats. On the other hand, there was a highly significant reduction of synthesis in the FRL rats treated by AGN-2979, relative to the vehicle group. Together, the results demonstrate that in the FSL rats, AGN-2979 does not affect serotonin synthesis. This suggests that there was no activation of TPH in the FSL rats during the experimental procedure, but such activation did occur in the FRL rats. Because of this finding, it could be hypothesised that TPH in the FSL rats cannot be easily activated. This may contribute to the development of depressive-like symptoms in the FSL rats ("depressed" rats), as they cannot easily modulate their need for elevated amounts of this Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access

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Open Channel Block of Kv3.1 Currents by Fluoxetine

Cited by 41 publications

References 34 publications

Effect of psoralen on the cloned Kv3.1 currents

Effect of psoralen on the cloned Kv3.1 currents

Inhibitory Action of Fluvoxamine on Kv1.5 Currents

AGN-2979, an inhibitor of tryptophan hydroxylase activation, does not affect serotonin synthesis in Flinders Sensitive Line rats, a rat model of depression, but produces a significant effect in Flinders Resistant Line rats

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