Clomipramine block of the hERG K+ channel: Accessibility to F656 and Y652

Jo, Su‐Hyun; Hong, Hee-Kyung; Chong, Seon Ha; Won, Kwang Hee; Jung, Sung Jun; Choe, Han

doi:10.1016/j.ejphar.2008.06.094

Cited by 26 publications

(14 citation statements)

References 25 publications

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“…Therefore, the I hERG in the absence of Pb 2+ is voltage dependent. The results are similar to those reported previously [18][19][20]. Currentvoltage relationship (I-V) curves of the stable and tail I hERG in the presence of 0, 50, 100, 150, 200, and 400 μg L −1 Pb 2+ were obtained from Fig.…”

Section: Resultssupporting

confidence: 54%

Effect of Lead Ion on the Function of the Human Ether-À-Go-Go-Related Gene K+ Channel

Zhou

2010

Biol Trace Elem Res

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Lead (Pb) is a trace metal element in the human body. In order to understand the hazard mechanism of the elevated blood lead level on the human body, the effect of Pb(2+) on the human ether-à-go-go-related gene (hERG) K(+) channel in the HEK 293 cell was investigated for the first time using whole-cell patch clamp technique, molecular dynamics simulation, and quantum chemistry calculation methods. We found that Pb(2+) obviously inhibits the current of the hERG K(+) channel, and delays the "activation" and "deactivation" of the hERG K(+) channel, indicating that Pb(2+) evidently decreases the function of the K(+) channel in the cell. The effect is increased with increasing the concentration of Pb(2+). When the concentration of Pb(2+) is 400 μg L(-1), the function of the K(+) channel is entirely lost. The results from the molecular dynamics simulation and quantum chemistry calculation indicated that Pb(2+) can coordinate with the oxygen/sulfur atoms in the K(+) channel protein, leading to the decrease in the function of the K(+) channel. According to the experimental results, we suggested that once the K(+) channel in the human body was irreversibly inactivated by Pb(2+), it would affect the treatment and prognosis of Pb(2+) intoxication.

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Section: Resultssupporting

confidence: 54%

Effect of Lead Ion on the Function of the Human Ether-À-Go-Go-Related Gene K+ Channel

Zhou

2010

Biol Trace Elem Res

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“…Data are expressed as means±SEM lobeline was obtained. This δ value for lobeline is larger than those observed for other open-channel blockers of Kv1.5 channels: quinidine (δ=0 19),. BIM (δ=0 19),.…”

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confidence: 52%

“…The cells were cultured in 50-ml polystyrene culture flasks in Iscove's modified Dulbecco's medium (Invitrogen) supplemented with 10% fetal bovine serum, 2 mM glutamine, 0.1 mM hypoxanthine, 0.01 mM thymidine, and 0.3 mg/ml geneticin (Invitrogen). The HERG cDNA was transferred into the plasmid expression vector pcDNA3 (Invitrogen) [19]. HEK293 cells (American Type Culture Collection) were stably transfected with HERG cDNA using the Lipofectamine reagent (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

Effects of lobeline, a nicotinic receptor ligand, on the cloned Kv1.5

Jeong

Choi

Hahn

2010

Pflugers Arch - Eur J Physiol

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The goal of the present study was to examine the effects of lobeline, an agonist at nicotinic receptors, on cloned Kv channels, Kv1.5, Kv3.1, Kv4.3, and human ether-a-gogo-related gene (HERG), which are stably expressed in Chinese hamster ovary (CHO) or human embryonic kidney 293 (HEK293) cells. Whole-cell patch-clamp experiments revealed that lobeline accelerated the decay rate of Kv1.5 inactivation, decreasing the current amplitude at the end of the pulse in a concentration-dependent manner with a half-maximal inhibitory concentration (IC(50)) value of 15.1 μM. Using a time constant for the time course of drug-channel interaction, the apparent association (k(+1)), and dissociation rate (k(-1)) constants were 2.4 μΜ(-1) s(-1) and 40.9 s(-1), respectively. The calculated K(D) was 17.0 μΜ. Lobeline slowed the decay rate of the tail current, resulting in a tail crossover phenomenon. The inhibition of Kv1.5 by lobeline steeply increased at potentials between -10 and +10 mV, which corresponds to the voltage range of channel activation. At more depolarized potentials a weaker voltage dependence was observed (δ=0.26). The voltage dependence of the steady-state activation curve was not affected by lobeline, but lobeline shifted the steady-state inactivation curve of Kv1.5 in the hyperpolarizing direction. Lobeline produced use-dependent inhibition of Kv1.5 at frequencies of 1 and 2 Hz, and slowed the recovery from inactivation. Lobeline also inhibited Kv3.1, Kv4.3, and HERG in a concentration-dependent manner, with IC(50) values of 21.7, 28.2, and 0.34 μM, respectively. These results indicate that lobeline produces a concentration-, time-, voltage-, and use-dependent inhibition of Kv1.5, which can be interpreted as an open-channel block mechanism.

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“…Third, a strong voltage-dependent block of IHERG by CsA was observed between −20 and 0 mV in the voltage ranges of the HERG channel opening (Fig. 4) In open-channel blocking mechanisms, a strong voltage dependence has been detected in the voltage range of the channel opening [22,23]. However, in the voltage range where the HERG channel is fully activated, an additional voltage dependence may be governed by the charged or uncharged form of the drug.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Actions of HERG Currents by the Immunosuppressant Drug Cyclosporin A

Lee

Hahn

Min

et al. 2011

Korean J Physiol Pharmacol

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The effect of cyclosporin A (CsA), an immunosuppressant, on human ether-a-go-go-related gene (HERG) channel as it is expressed in human embryonic kidney cells was studied using a whole-cell, patch-clamp technique. CsA inhibited the HERG channel in a concentration-dependent manner, with an IC50 value and a Hill coefficient of 3.17μ M and 0.89, respectively. Pretreatment with cypermethrine, a calcineurin inhibitor, had no effect on the CsA-induced inhibition of the HERG channel. The CsA-induced inhibition of HERG channels was voltage-dependent, with a steep increase over the voltage range of the channel opening. However, the inhibition exhibited voltage independence over the voltage range of fully activated channels. CsA blocked the HERG channels predominantly in the open and inactivated states rather than in the closed state. Results of the present study suggest that CsA acts directly on the HERG channel as an open-channel blocker, and it acts independently of its effect on calcineurin activity.

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Clomipramine block of the hERG K+ channel: Accessibility to F656 and Y652

Cited by 26 publications

References 25 publications

Effect of Lead Ion on the Function of the Human Ether-À-Go-Go-Related Gene K+ Channel

Effect of Lead Ion on the Function of the Human Ether-À-Go-Go-Related Gene K+ Channel

Effects of lobeline, a nicotinic receptor ligand, on the cloned Kv1.5

Inhibitory Actions of HERG Currents by the Immunosuppressant Drug Cyclosporin A

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